AIDS is the disease caused by infection with HIV and is characterized by profound immunosuppression with associated opportunistic infections and malignant tumors, wasting, and neurocognitive disorders. HIV primarily infects activated CD4+ helper T cells. Macrophages and DCs can also harbor the virus but are less likely to be infected than activated CD4+ T cells. HIV emerged as a human pathogen recently relative to most other known human pathogens, and the HIV epidemic was first identified in the 1980s. However, the degree of morbidity and mortality caused by HIV and the global impact of this infection on healthcare resources and economies are enormous. HIV has infected more than 80 million people and has caused the death of more than 40 million adults and children. Approximately 39 million people are living with HIV infection, of which approximately 66% are in Africa and 17% in Asia, and more than half a million people die of the disease every year. An especially devastating feature of the disease is that half of the approximately 3 million new cases every year occur in young adults (less than 15 years old). AIDS has left approximately 16 million orphans. About 1.5 million children under 15 have HIV and more than 90% of these children acquired AIDS from their mothers during fetal life, childbirth, or while breastfeeding. About 100,000 children die of AIDS every year. Currently, there is no vaccine or permanent cure for AIDS, but antiretroviral drugs are in use that are effective at controlling the infection and taking preventative antiretroviral therapy has had significant impact on transmission from an HIV+ to HIV- sexual partner.
Transmission of HIV and Epidemiology of AIDS
The viral particles that initiate infection are usually in the blood, semen, or other body fluids of an infected individual and are introduced into another individual by three main routes.
• Sexual contact is the most frequent mode of transmission, either between heterosexual couples (the most frequent mode of transmission in Africa and Asia) or between men having sex with men and their sexual partners. In sub Saharan Africa, where the infection rate is the highest in the world (estimated to be several thousand new cases every day), more than half the infected individuals are women.
• Mother-to-child transmission of HIV accounts for the majority of pediatric cases of AIDS. This type of transmission occurs most frequently in utero or during childbirth, although transmission through breast milk is also possible.
• Inoculation of a recipient with infected blood or blood products is also a frequent mode of HIV transmission. Needles shared by intravenous drug users account for most cases of this form of transmission. HIV can remain infectious in a used infected needle for 6 weeks in temperate climates. With the advent of routine laboratory screening, transfusion of blood, or blood products, in a clinical setting accounts for a negligible proportion of HIV infections.
An Overview of HIV Virology
HIV is a member of the lentivirus family of animal retroviruses. Two closely related types of HIV, designated HIV-1 and HIV-2, have been identified. HIV-1 is by far the most common cause of AIDS; HIV-2, which differs in genomic structure and antigenicity, causes a form of AIDS with slower progression than HIV-1 linked disease and is mainly confined to West Africa, though it is present worldwide.
HIV Structure and Genes
An infectious HIV particle consists of two identical strands of RNA packaged within a core of viral proteins and surrounded by a phospholipid bilayer envelope derived from the host cell mem brane but including virally encoded membrane proteins (Fig. 1). The RNA genome of HIV is approximately 9.2 kb long and has the basic arrangement of nucleic acid sequences characteristic of all known retroviruses. Long terminal repeats (LTRs) at each end of the genome regulate viral gene expression, viral integration into the host genome, and viral replication. The gag sequence encodes core structural proteins. The env sequence encodes the HIV Envelope (Env) protein. Env exists as a trimer of three molecules of a glycoprotein, gp120, and a stem of three molecules of gp41 that is inserted in the viral lipid bilayer. The pol sequence encodes reverse transcriptase, integrase, and viral protease enzymes, which are required for viral replication. In addition to these typical retrovirus genes, the HIV-1 genome contains six other regulatory genes unique to HIV, named the tat, rev, vif, nef, vpr, and vpu genes, whose products regulate viral replication and host immune evasion in various ways. The functions of these genes are discussed later.
Fig1. Structure of human immunodeficiency virus 1 (HIV-1). An HIV-1 virion is shown next to a T-cell surface. HIV-1 consists of two identical strands of RNA (the viral genome) and associated enzymes, including reverse transcriptase, integrase, and protease, packaged in a cone-shaped core composed of p24 capsid protein with a surrounding p17 protein matrix, all surrounded by a phospholipid membrane envelope derived from the host cell. Virally encoded membrane proteins (gp41 and gp120) are bound to the envelope. CD4 and chemokine receptors on the host cell surface function as HIV-1 receptors. (Adapted from ©1996 Terese Winslow.)
Viral Life Cycle
HIV infection of cells begins when the envelope glycoprotein gp120 of the virus binds to two proteins on host cells: CD4 and a chemokine receptor that functions as a coreceptor (Fig. 2). The Env complex mediates fusion of the virion with the target cell. The first step of this process is the binding of gp120 subunits to CD4 molecules, which promotes gp120 binding to a chemokine receptor, generally CCR5 or CXCR4. HIV binding to the coreceptor induces a conformational change in gp41, its refolding into a six-helix bundle that exposes a hydrophobic region called the fusion peptide, which then inserts into the cell membrane and enables the viral membrane to fuse with the target cell membrane. After the virus completes its life cycle in the infected cell (described later), free viral particles are released from the infected cell and bind to an uninfected cell, thus propagating the infection.
Fig2. Human immunodeficiency virus (HIV) life cycle. The sequential steps in the life cycle of HIV are shown, from initial infection of a host cell to viral replication and release of a new virion. For the sake of clarity, the production and release of only one new virion are shown. An infected cell actually produces many virions, each capable of infecting cells, thereby amplifying the infectious cycle.
The most important chemokine receptors that act as coreceptors for HIV are CCR5 and CXCR4. However, more than seven different chemokine receptors have been shown to serve as coreceptors for HIV entry into cells. The importance of CCR5 in HIV infection in vivo is supported by the finding that individuals who do not express this receptor on the cell surface because of an inherited homozygous deletion in the CCR5 gene are resistant to HIV infection.
After an HIV virion enters a cell, the enzymes within the nucleoprotein complex become active and begin the viral replication cycle (see Fig. 2). The nucleoprotein core of the virus becomes disrupted, its RNA genome is reverse transcribed into double-stranded DNA by viral reverse transcriptase, and the viral DNA enters the nucleus. The viral integrase also enters the nucleus and catalyzes the integration of viral DNA into the host cell genome. The integrated HIV DNA is called the provirus. The provirus may remain transcriptionally inactive for months or years, with little or no production of new viral proteins or virions, and in this way HIV infection of an individual cell can be latent.
Transcription of the genes of the integrated DNA provirus is regulated by the LTR upstream of the viral structural genes, and cytokines and other stimuli that activate T cells and macrophages enhance viral gene transcription. Initiation of HIV gene transcription in T cells is stimulated by the viral Tat protein and is linked to activation of the infected T cells by antigen or cytokines. Thus, the normal response of a latently infected T cell to a microbe may be the way in which HIV latency is ended and virus production begins.
Synthesis of mature infectious viral particles begins after full-length viral RNA transcripts are produced and the viral genes are expressed as proteins. The mRNAs encoding the various HIV proteins are derived from a single full-genome length transcript by differential splicing events. HIV gene expression may be divided into two stages. The Rev, Tat, and Nef proteins are early gene products encoded by fully spliced mRNAs that are exported from the nucleus and translated into proteins in the cytoplasm soon after infection of a cell. Late expressed genes include env, gag, and pol, which encode the structural components of the virus and are translated from singly spliced or unspliced RNA. The Rev protein initiates the switch from early to late gene expression by promoting the export of these incompletely spliced late gene RNAs out of the nucleus. The pol gene product is a precursor protein that is sequentially cleaved to form reverse transcriptase, protease, ribonuclease, and integrase enzymes. The gag gene encodes a precursor protein that is cleaved into several polypeptides including the abundant p24 capsid protein, by the viral protease encoded by the pol gene. These gag-derived proteins are required for the assembly of infectious viral particles. The primary product of the env gene is gp160, which is cleaved by cellular proteases within the endoplasmic reticulum into the gp120 and gp41 proteins required for HIV binding to cells. Current antiviral drug therapy for HIV disease includes inhibitors of the reverse transcriptase, protease, and integrase.
After the transcription of various viral genes, viral proteins are synthesized in the cytoplasm. Assembly of infectious viral particles then begins by packaging full-length RNA transcripts of the proviral genome within a nucleoprotein complex required for the next cycle of integration. This nucleoprotein complex then buds from the plasma membrane.
Pathogenesis of HIV Infection and AIDS
HIV disease begins with acute infection, which is only partly controlled by the host immune response, and advances to chronic progressive infection of peripheral lymphoid tissues (Fig. 3). The virus typically enters through mucosal epithelia. The subsequent events in the infection can be divided into several phases.
Fig3. Progression of human immunodeficiency virus (HIV) infection. The progression of HIV infection correlates with the spread of the virus from the initial site of infection to lymphoid tissues throughout the body. The immune response of the host temporarily controls acute infection but does not prevent the establishment of chronic infection of cells in lymphoid tissues. Cytokine stimuli induced by other microbes serve to enhance HIV production and progression to acquired immunodeficiency syndrome (AIDS). CTLs, Cytotoxic T lymphocytes.
Acute (early) infection is characterized by infection of activated CD4+ T cells in mucosal lymphoid tissues and the death of many infected CD4+ T cells. A large number of activated and memory CD4+ T cells reside at mucosal sites, primarily in the gastrointestinal tract, and can be infected by HIV. Within 2 to 4 weeks of infection, a large fraction of mucosal CD4+ T cells may be destroyed.
The transition from the acute phase to the chronic phase of infection is accompanied by dissemination of the virus, viremia, and development of host adaptive immune responses. DCs in epithelia at sites of virus entry capture the virus and then migrate into the lymph nodes. Once in lymphoid tissues, DCs may pass HIV on to CD4+ T cells through direct cell-cell con tact. Within days after the first exposure to HIV, viral replication can be detected in the lymph nodes and gut lymphoid tissues. This replication leads to viremia, during which large numbers of HIV particles are present in the patient’s blood, accompanied by an acute HIV syndrome that includes a variety of nonspecific signs and symptoms. As the HIV infection spreads, the adaptive immune system mounts both humoral and cell-mediated immune responses directed at viral antigens, which we will describe later. These immune responses partially control the infection and viral production, and such control is reflected by a drop in viremia to low but detectable levels by approximately 12 weeks.
In the next, chronic, phase of the disease, lymph nodes, the spleen, and the gastrointestinal tract are sites of continuous HIV replication and cell destruction (see Fig. 3). During this period of the disease, the immune system remains competent at handling most infections with opportunistic microbes, and few or no clinical manifestations of the HIV infection are present. Therefore, this phase of HIV disease is called the clinical latency period, during which viral replication is at low levels. Although the majority of peripheral blood T cells do not harbor the virus, destruction of CD4+ T cells within lymphoid tissues steadily progresses during the latent period, and the number of circulating blood CD4+ T cells steadily declines (Fig. 4). More than 90% of the body’s approximately 1012 T cells are normally found in peripheral and mucosal lymphoid tissues, and it is estimated that HIV destroys up to 1 to 2 × 109 CD4+ T cells every day. Early in the course of the disease, the infected individual may continue to make new CD4+ T cells, and therefore these cells can be replaced almost as quickly as they are destroyed. At this stage, up to 10% of CD4+ T cells in lymphoid organs may be infected, but the number of circulating CD4+ T cells that are infected at any one time may be less than 0.1% of the total CD4+ T cells in the blood. Eventually, over a period of years, the continuous cycle of virus infection, T-cell death, and new infection leads to an inexorable loss of CD4+ T cells from the lymphoid tissues and the circulation.
Fig4. Clinical course of human immunodeficiency virus (HIV) disease. (A) Plasma viremia, blood CD4+ T-cell counts, and clinical stages of disease. Approximately 12 weeks after infection, the blood-borne virus (plasma viremia) is reduced to very low levels (detectable only by sensitive reverse transcriptase-polymerase chain reaction assays) and stays this way for many years. Nonetheless, CD4+ T-cell counts steadily decline during this clinical latency period because of active viral replication and T-cell infection in lymph nodes. When CD4+ T-cell counts drop below a critical level (∼200/mm3), the risk for infection and other clinical features of acquired immunodeficiency syndrome is high. (B) Immune response to HIV infection. A cytotoxic T lymphocyte (CTL) response to HIV is detectable by 2–3 weeks after the initial infection and peaks by 9–12 weeks. Marked expansion of virus-specific CD8+ T cells occurs during this time, and up to 10% of a patient’s CTLs may be HIV specific at 12 weeks. The humoral immune response to HIV peaks at about 12 weeks. (A, From Pantaleo G, Graziosi C, Fauci AS. New concepts in the immunopathogenesis of human immunodeficiency virus infection. N Engl J Med. 1993;328:327–335.)
Mechanisms of Immunodeficiency Caused by HIV
HIV infection ultimately results in impaired function of both the adaptive and innate immune systems. The most prominent defects are in cell-mediated immunity, which result mainly from the destruction of CD4+ T cells. Both infected and possibly noninfected CD4+ T cells may be lost.
A major cause of the loss of CD4+ T cells in HIV-infected individuals is the direct cytopathic effect of infection of these cells by HIV. Death of CD4+ T cells is associated with production of virus in infected cells and may contribute to the decline in the numbers of these cells. Several direct toxic effects of HIV on infected CD4+ cells have been described.
• The process of virus production, with expression of gp41 in the plasma membrane and budding of viral particles, may lead to increased plasma membrane permeability and the influx of lethal amounts of calcium, which induces apoptosis, or osmotic lysis of the cell caused by the influx of water.
• Viral production can interfere with cellular protein synthesis and thereby lead to cell death.
Mechanisms in addition to virus-induced death of infected CD4+ T cells have been proposed for the depletion and functional impairment of these cells in HIV-infected individuals.
• Chronic activation of uninfected cells by the infections that are common in HIV-infected individuals may culminate in apoptotic death of the uninfected cells (sometimes called activation-induced cell death). This may account for the observation that the loss of T cells greatly exceeds the number of HIV-infected cells.
• HIV-specific CTLs may kill HIV-infected CD4+ T cells.
• The accumulation of viral DNA may activate inflammasomes and cause pyroptosis, a lytic form of cell death.
• Infected and noninfected cells may fuse, forming multinucleated giant cells.
• Antibodies against HIV envelope proteins may bind to HIV infected CD4+ T cells, targeting the cells for ADCC.
The relative importance of these and other indirect mechanisms of CD4+ T-cell depletion in HIV-infected patients is uncertain and controversial.
Functional defects in the immune system of HIV-infected individuals exacerbate the immune deficiency caused by depletion of CD4+ T cells. These functional defects include a decrease in T-cell responses to antigens and nonneutralizing and less vigorous humoral immune responses, even though total serum Ig levels may be elevated. Numerous mechanisms have been proposed. CD4 that has bound gp120 may not be available to interact with MHC class II molecules on APCs and thus T-cell responses to antigens would be inhibited. Also, gp120 binding to CD4 may deliver signals that downregulate helper T-cell function. Some studies have demonstrated that patients with HIV infection have increased numbers of CD4+CD25+ regulatory T cells, but it is not yet clear if this is a consistent finding or if these cells actually contribute to defective immunity. HIV patients experience CD8+ T-cell exhaustion, in the context of ongoing antigen stimulation and inflammation, which impairs CD8+ T cell effector function.
While HIV does not infect B cells, there are impacts on B cells in patients with HIV. For example, there is polyclonal B cell activation, which causes hyperplasia of germinal center B cells. This may result in autoimmunity. This is thought to potentially be caused by EBV reactivation, IL-6 released by HIV-infected macrophages and/or gp41 leading to B cell growth and differentiation. In addition, there is an increase in the number of plasma cells, which can cause increased levels of IgG (hypergammaglobulinemia). Of note, while there may be more B cells there is also poor B-cell function, which may be secondary to T-cell deficiency or due to impaired B-cell function.
HIV Reservoirs and Viral Turnover
More than 90% of plasma virus is thought to be produced by activated and memory CD4+T cells that are major reservoirs and sources of the virus in infected patients. About two-thirds of the HIV reservoir exists in the mucosal immune system, mainly in the gastrointestinal tract, and about one-third is in lymph nodes. Although there are ongoing attempts to enhance host immunity and clear the virus completely from infected individuals (often referred to as an HIV cure), the resilience of the HIV reservoir has proved a confounding factor. Many latent viruses within the reservoir remain relatively protected from the host immune system.
• Because macrophages can be infected but are not generally killed by HIV, they may become a reservoir for the virus. In fact, the quantity of macrophage-associated HIV exceeds T cell–associated virus in some tissues from patients with AIDS, notably the brain. HIV-infected macrophages may be impaired in antigen presentation functions and cytokine secretion.
• Follicular dendritic cells (FDCs) in the germinal centers of lymph nodes and the spleen trap large amounts of HIV on their surfaces, in part by Fc receptor–mediated binding of antibody-coated virus. They may also transmit the virus to T follicular helper (Tfh) cells. Germinal centers are thought to be protected from CTLs. Also, loss of FDCs, which remains poorly understood, may lead to dissolution of the architecture of secondary lymphoid organs.
• It is hypothesized that a very small fraction of the virus, perhaps as little as 1%, is present in latently infected memory T cells. Because of the long life span of memory cells, it could take decades for this reservoir of virus to be eliminated, even if all new rounds of infection were blocked.
Clinical Course of HIV Infection
The course of HIV disease can be followed by measuring the amount of virus in the patient’s plasma and by the blood CD4+ T-cell count (see Fig. 4). Three phases of the disease are recognized.
• The acute phase, also called acute HIV syndrome, is the period of viremia characterized by nonspecific symptoms of infection. It develops in 50% to 70% of infected adults typically 3 to 6 weeks after infection. There is a spike of plasma virus and a modest reduction in CD4+ T-cell counts, but the number of blood CD4+ T cells often returns to normal. In many patients, however, the infection is occult and there are no symptoms.
• The phase of clinical latency may last for many years. During this time, the virus is contained within lymphoid tis sues and the loss of CD4+ T cells is corrected by replenishment from progenitors. Patients are asymptomatic or suffer from minor infections. Within 2 to 6 months after infection, the concentration of plasma virus stabilizes at a particular set point, which differs among patients. The level of the viral set point and the number of blood CD4+ T cells are clinically useful predictors of the progression of disease. As the disease progresses, patients become susceptible to other infections, and immune responses to these infections may stimulate HIV production and accelerate the destruction of lymphoid tissues. As discussed earlier, HIV gene transcription can be enhanced by stimuli that activate infected T cells, such as antigens and various cytokines. Cytokines, such as TNF, which are produced during the innate immune response to microbial infections, are particularly effective in boosting HIV production. Thus, as the immune system attempts to eradicate other microbes, it brings about its own destruction by HIV, a tragic example of what has been called subversion from within.
• HIV disease progresses to the final phase, called AIDS, when the blood CD4+ T-cell count drops below 200 cells/mm3. HIV viremia may climb dramatically as viral replication accelerates unchecked in reservoirs other than T cells. Patients with AIDS suffer from combinations of opportunistic infections, neoplasms, cachexia (HIV wasting syndrome), kidney failure (HIV nephropathy), and CNS disease (AIDS encephalopathy, now called HIV-associated neurocognitive disorder, or HAND) (Table 1). Because CD4+ helper T cells are essential for both cell-mediated and humoral immune responses to various microbes, the loss of these lymphocytes is the main reason that patients with AIDS become susceptible to many different types of infections. Furthermore, many of the tumors that arise in patients with AIDS have a viral cause, and their prevalence in the setting of AIDS reflects an inability of the HIV-infected patient to mount an effective immune response against oncogenic viruses. Cachexia is often seen in patients with chronic inflammatory diseases and may result from effects of inflammatory cytokines (such as TNF) on appetite and metabolism. The CNS disease in AIDS may be due to neuronal damage by the virus or by shed viral proteins, such as gp120 and Tat, as well as the effects of cytokines elaborated by infected microglial cells.
Table1. Clinical Features of HIV Infection
Although this summary of the clinical course is true for the most severe cases, the rate of progression of the disease is highly variable, and some individuals are long-term nonprogressors. The possible mechanisms underlying long-term nonprogression are described later. Importantly, antiretroviral therapy (ART), which is now increasingly available, has changed the course of the disease and greatly reduced the incidence of severe opportunistic infections (such as Pneumocystis) and tumors (such as Kaposi sarcoma).
Immune Responses to HIV
Innate Immunity to HIV
HIV is sensed by a number of pattern recognition receptors, including TLRs and RIG-I. Two key sensors that recognize viral reverse transcription products early in infection are IFI16 (interferon inducible protein 16) and cGAS (cyclic GMP-AMP synthase), both discussed in Chapter 4. IFI16 can bind to HIV derived DNA and signals via the STING (stimulator of IFN genes) adaptor, the TBK1 protein kinase, and the IRF3 and IRF7 transcription factors. This signaling induces type I IFN production and the expression of host restriction factors such as APOBEC3 and tetherin.
Many innate immune responses against HIV have been described. These include production of antimicrobial peptides (defensins) and activation of NK cells, DCs (particularly plasma cytoid DCs producing type I IFNs), and the complement system.
Adaptive Immune Responses to HIV
HIV-specific humoral and cell-mediated immune responses develop after infection but generally provide limited protection. The early immune response to HIV infection is, in fact, similar to the response to other viruses and serves to clear most of the virus present in the blood and in circulating T cells. Nonetheless, it is clear that these immune responses fail to eradicate HIV, and the infection eventually overwhelms the immune system in most untreated individuals. Despite the poor effectiveness of antiviral immune responses, it is important to characterize them for three reasons. First, the immune responses may be detrimental to the host, for example, by stimulating the uptake of opsonized virus into uninfected cells by Fc receptor–mediated endocytosis. Second, antibodies against HIV are diagnostic markers of HIV infection that are widely used for screening purposes. Third, the design of effective vac cines for immunization against HIV requires knowledge of the types of immune responses that are most likely to be protective (the immunologic correlates of protection).
The initial adaptive immune response to HIV infection is characterized by expansion of CD8+ T cells specific for HIV peptides. As many as 10% or more of circulating CD8+ T cells may be specific for HIV gag and other viral proteins during acute infection. These CTLs control infection in the early phase (see Fig. 4) but ultimately prove ineffective because of the emergence of viral escape mutants (variants with mutated anti gens). CD4+ T cells also respond to the virus and these CD4+ T cells may contribute to viral control in a number of ways. An effective CD4+ T-cell response is required as a source of help for the generation of CD8+ memory T cells, but CD4+ T cells have also been shown to kill HIV-infected cells. The importance of CTL responses in HIV control is underscored by the evolution of the virus under immune pressure, resulting in viral isolates that have lost their original CTL epitopes. The evolution of the virus also results in the loss of epitopes recognized by CD4+ T cells, indicating that both CD8+ and CD4+ cells contribute to host defense against the virus.
Antibody responses to a variety of HIV antigens are detect able within 6 to 9 weeks after infection. The most immunogenic HIV molecules that elicit antibody responses appear to be the envelope glycoproteins, and high titers of anti-gp120 and anti gp41 antibodies are present in most HIV-infected individuals. Other anti-HIV antibodies found frequently in patients’ sera include antibodies to p24, reverse transcriptase, and gag and pol products. The effect of these antibodies on the clinical course of HIV infection is uncertain. The early antibodies are generally not neutralizing and are thus poor inhibitors of viral infectivity or cytopathic effects. Neutralizing antibodies against gp120 develop 2 to 3 months after primary infection, but even these antibodies cannot cope with a virus that is able to rap idly change the most immunodominant epitopes of its envelope glycoproteins. Intriguingly, for unknown reasons, only approximately 10% to 15% of chronically infected individuals develop broadly neutralizing antibodies. These antibodies bind to a site on a viral protein that the virus cannot afford to mutate, such as the CD4-binding site of gp140. They are, therefore, effective in clearing the virus. A striking feature of all these antibodies is that they have been selected after extensive somatic hypermutation, implying helper T cell–dependent antibody responses. The implication is that the starting naive HIV-specific B-cell repertoire consists primarily of B cells whose antigen receptors bind weakly to certain antigenic epitopes, such as the CD4-binding site of gp140. Many rounds of somatic hypermutation and selection that may occur in a long-standing infection can eventually generate B-cell populations that bind with high affinity to the original weakly recognized epitope. One of the goals of vaccination is to generate such high-affinity broadly neutralizing antibodies, which are able to neutralize diverse HIV strains, but inducing the high rate of somatic hypermutation necessary to achieve this has proved a challenge, and this has not yet been achieved with any consistency.
Mechanisms of Immune Evasion by HIV
HIV is the prototype of an infectious pathogen that evades host defenses by destroying the immune system. We have earlier considered some mechanisms by which this virus evades host restriction factors and innate immunity. In addition, several features of HIV may help the virus to evade adaptive immunity.
HIV has an extremely high mutation rate because of error prone reverse transcription, and in this way, as well by using other immune evasion strategies, it may evade detection by antibodies or T cells generated in response to viral proteins. A region of the gp120 molecule, called the V3 loop, is one of the most antigenically variable parts of the virus; it differs even in HIV isolates taken from the same individual at different times. Many epitopes of the virus that could potentially serve as targets for broadly neutralizing antibodies are also shielded by bulky N-linked sugars, that make up what is known as the HIV-glycan shield.
HIV-infected cells may evade CTLs through downregulation of MHC class I molecule expression. The HIV Nef protein inhibits expression of MHC class I molecules, mainly by promoting internalization of these molecules. Other mechanisms of inhibiting cell-mediated immunity have been demonstrated in some cases.
Elite Controllers and Long-Term Nonprogressors: A Possible Role for Host Genes
Although most individuals infected with HIV and not given anti viral therapy eventually develop AIDS, approximately 1% of individuals who are infected do not develop clinical disease. Such individuals maintain high CD4+ and CD8+ T-cell counts, do not require therapy, and may have persistent viremia but no disease for at least 10 to 15 years. On the basis of the degree of viremia, this group can be divided into two subsets: long-term nonprogressors have detectable viremia of approximately 5000 copies of HIV-1 RNA per milliliter of blood, and a much smaller subset of elite con trollers maintain viral loads of approximately 50 copies or less of HIV-1 RNA per milliliter of blood. There is considerable interest in understanding the genetic basis of HIV control by examining these cohorts of individuals in detail. So far, a role for the MHC locus in protecting individuals and preventing progression has been suggested by genetic association studies. Specific HLA class I loci have been linked to the absence of disease progression. Some elite con trollers generate strong CD8+ T-cell responses to highly conserved peptides in the virus so that the virus cannot mutate without losing infectivity. We have previously mentioned the importance of the inheritance of the CCR5 homozygous 32-bp deletion in protection from infection, and other genetic factors contributing to resistance are likely to be revealed in the coming years.
Treatment and Prevention of AIDS and Vaccine Development
Active research efforts have been aimed at developing drugs that interfere with the viral life cycle. Treatment of HIV infection and AIDS now typically involves the administration of three antiviral drugs, used in combination, that target viral molecules for which no human homologs exist. The first antiretroviral drugs to be widely used were nucleoside analogs that inhibit viral reverse transcriptase. These drugs include deoxythymidine nucleoside ana logs such as AZT (3′-azido-3′-deoxythymidine), deoxycytidine nucleoside analogs, and deoxyadenosine analogs. Nonnucleoside reverse transcriptase inhibitors directly bind to the enzyme and inhibit its function. Viral protease inhibitors have been developed that block the processing of precursor proteins into mature viral capsid and core proteins. When nucleoside analogs or pro tease inhibitors are used alone, mutant viruses resistant to their effects emerge. However, protease inhibitors are now a common component of a three-drug therapeutic regimen with two different reverse transcriptase inhibitors. This triple-drug therapy, commonly referred to as highly active antiretroviral therapy or ART, has proved to be effective in reducing plasma viral RNA to undetectable levels in most treated patients for years. An integrase inhibitor is now also available for antiviral therapy. Entry inhibitors, which prevent viral entry by targeting either CD4 or CCR5 on the host cell are another novel category of therapeutics. Fusion inhibitors are drugs that target gp41 and prevent fusion of the viral envelope with the host cell plasma membrane.
Although ART has reduced viral titers to below detection for up to 10 years in some patients, it is unlikely that such treatment can eliminate the virus from all reservoirs (especially long-lived infected cells) and resistance to the drugs may ultimately develop. Other formidable problems associated with these new drug therapies, which will impair their effective use in many parts of the world, include high expense and significant adverse effects. Furthermore, in some patients the virus evolves to become resistant to the drugs being used. Inconsistent use of these drugs by patients is also a major problem. Preexposure prophylaxis (PrEP) using a single pill or that contains two mechanistically different reverse transcriptase inhibitors or an injectable integrase strand inhibitor that is given every two months are designed to protect individuals who do not have HIV but who are at high risk for getting the disease. When used routinely, PrEP has been effective, but the rollout of PrEP has experienced challenges in blunting the impact of the epidemic in those parts of the world where the need is greatest.
A proportion of patients receiving ART experience an aberrant manifestation of immune reconstitution, namely overexuberant inflammation that may be triggered by the recognition by the immune system of preexisting pathogens. It usually accompanies the restoration of CD4+ T-cell counts and a decline in viral load. This clinical phenomenon is called the immune reconstitution inflammatory syndrome.
The infections experienced by patients with AIDS are pre vented with prophylaxis, and if necessary, treated with the appropriate antibiotics and supportive measures. More aggressive antibiotic therapy is often required than for similar infections in less compromised hosts.
Although ART has led to longer survival rates after HIV infection, chronic HIV infection is associated with an increased risk for non-AIDS-related morbidity and mortality than seen in age-matched uninfected individuals. In these patients there is a well-documented increase in cardiovascular disease, liver dis orders, disorders of neurocognition, kidney disease, and some cancers. Chronic HIV is now recognized as a chronic inflammatory disease with manifestations that may be linked to local or systemic inflammation.
Efforts at prevention of HIV infection are extremely important and potentially effective in controlling the HIV epidemic. In the United States, the routine screening of blood products for evidence of donor HIV infection has already reduced the risk transmission through blood transfusion to negligible levels. Various public health measures to increase condom use and to reduce the use of contaminated needles by intravenous drug users are now widespread. Administration of antiretroviral drugs to pregnant mothers is effective at preventing infection of the newborns. Prophylactic use of these drugs in high-risk patients also reduces the rate of infection, as mentioned.
The development of an effective vaccine against HIV remains a priority. The task has been complicated by the ability of the virus to mutate and vary many of its immunogenic antigens. It is likely that an effective vaccine will have to stimulate both humoral and cell-mediated responses to viral antigens. To achieve this goal, several approaches have been tried for HIV vaccine development. Various live virus vaccines have been tested in the hopes that they will induce strong CTL responses. Such vaccines include nonvirulent recombinant hybrid viruses composed of part-SIV and part-HIV sequences or viruses that have been attenuated by deletions in one or more parts of the viral genome. A concern with live virus vaccines is their potential to cause disease if they are not completely attenuated and possibly to recombine with wild-type HIV to produce a pathogenic variant. One promising approach is the use of live, recombinant non-HIV viral vectors carrying HIV genes, which can induce potent CTL responses.
Most current vaccination attempts are aimed at generating broadly neutralizing antibodies, which can prevent the infectivity of a large number of HIV strains. Such an antibody would have to recognize some part of gp120, such as the CD4-binding site, which is highly conserved. Human trials have so far not provided evidence for vaccine induced protection. Newer concepts include targeting B-cell precursors that are capable of producing broadly neutralizing antibodies, activating them, selecting for productive somatic mutations and then the production of memory B cells as well as optimal prime/boost and fractional escalating vaccine dose strategies. In addition, there is a renewed focus on driving T-cell responses. Other approaches for protection against HIV are under development. First, with the success of mRNA vaccines in combating the COVID-19 pandemic, there are multiple ongoing trials that have early encouraging preliminary data in HIV. Second, passive immunity with mixtures of broadly neutralizing antibodies, derived as described earlier, that have been recombinantly generated for clinical use.
