HIV-1 Infection Immunology: Ultimate Guide To HIV-1 Infection Immunology

HIV-1 Infection Immunology - The ultimate guide to HIV-1 Infection Immunology, including facts and information about HIV-1 Infection Immunology.

HIV-1 Infection Immunology - The Ultimate Guide To HIV-1 Infection Immunology


HIV-1 Infection Immunology: Introduction


The interactions of HIV-1 with the immune system contribute extensively to the pathogenesis of AIDS. These interactions are critical during . They also largely determine the rate of progression from primary HIV infection to AIDS, and underlie multiple mechanisms for the immunodeficiency that ensues. An understanding of the immunology of HIV-1 informs our current clinical management of patients with AIDS and fuels the development of novel strategies for prevention and treatment of HIV-1 infection or AIDS-related disease.



HIV-1 Infection Immunology: Primary Infection


HIV-1 targets several different cells of the human immune system, principally through interaction of the HIV-1 envelope glycoprotein, gp120, with two host cell surface receptors, CD4 and a chemokine receptor. CD4 is an important co-receptor for T cells involved in T-cell receptor recognition of exogenous antigens presented by major histocompatibility complex (MHC) class II molecules. Chemokines comprise a large family of soluble mediators that regulate movement of cells within the immune system. HIV-1 interacts variably with one of two chemokine receptors, called CXCR4 and CCR5. Chemokine receptor selectivity is determined by variable regions in gp120 that render HIV-1 strains tropic for either CXCR4, CCR5 or dual tropic. Both CXCR4 and CCR5 are expressed by CD4 T cells. CCR5 is also expressed by tissue macrophages and dendritic cells.



The majority of HIV-1 infection in vivo exists within CD4 T cells. There is also evidence for HIV-1 infection within tissue macrophages. There is less evidence for active HIV-1 replication within dendritic cells. Importantly, however, dendritic cells can also capture HIV-1 via a Ca2+-dependent lectin receptor called DC-SIGN. This does not trigger HIV-1 fusion and integration, but rather endocytosis of virus that is subsequently displayed at the cell surface. Importantly the interaction of DC-SIGN with HIV-1 stimulates so-called maturation and migration of dendritic cells to regional lymph nodes where HIV-1 on the surface of dendritic cells will encounter permissive CD4 T cells.



The current paradigm for the natural route of primary HIV-1 infection via mucosal surfaces therefore proposes that resident macrophages and dendritic cells may be the primary host cells targeted by HIV-1. They then propagate transmission of HIV-1 to T cells that are recruited locally or within regional lymph nodes. This model is supported by a variety of observations. Sexual HIV-1 transmission is significantly associated with concurrent inflammatory conditions of the recipient mucosa in which HIV-permissive macrophages and dendritic cells may be more abundant. In addition, HIV-1 strains isolated during primary infection are predominantly CCR5 or macrophage tropic, and CCR5-deficient individuals are relatively resistant to HIV-1 infection. Recent studies on HIV-1 founder viruses that establish successful infection confirm that these viruses are CCR5 tropic, but surprisingly unable to infect macrophages, suggesting that local T cells may in fact form the first founder population of infected cells.



HIV-1 Infection Immunology: Antiviral Host Immune Responses


The seroconversion illness that follows primary infection with HIV-1 coincides with a transient peak of viral replication. Patients' symptoms and the fall in HIV-1 viral load is ascribed to the antiviral host immune response. Non-specific (innate) interferon and specific (adaptive) humoral (antibody) and cellular immune responses to HIV-1 can be readily demonstrated at this time.



The cellular adaptive immune response to viral pathogens is principally mediated by CD8 cytotoxic T lymphocytes (CTLs) that recognize antigens presented by MHC class I at the surface of infected host cells. CTLs kill virus-infected cells by causing cell lysis. In most cases three or four separate CTL clones can be demonstrated that recognize different HIV-1 epitopes. During primary infection. the appearance of CTLs correlate temporally and quantitatively with the fall in HIV-1 viral load. Furthermore, greater numbers of CTLs and a broader repertoire of CTL clones both correlate with delay in disease progression and the onset of AIDS. The role of interferon (IFN) and antibody responses in the control of viraemia during primary HIV infection is less clear.



HIV-1 Infection Immunology: HIV-1 Evasion Of Host Immunity


Although IFN, antibody and CTL responses to HIV-1 may contribute to the initial control of HIV-1 viral load after primary infection, they do not establish sterilizing immunity. Viral replication continues and eventually overwhelms the immune response as patients develop AIDS. Immunological evasion underlies the ability of HIV-1 to cause persistent infection, avoid the development of natural protective immunity and resist extensive efforts to produce a protective vaccination strategy. Numerous mechanisms have been identified by which HIV-1 can evade the host immune system.



Protective antibodies are required to recognize the HIV-1 envelope. Anti-gp120 antibodies are produced by all patients, but in vivo, these antibodies are non-neutralizing, meaning that they are unable to clear the virus or prevent infection after vaccination. This is partly because gp120 associates with another glycoprotein, called gp41, in trimeric complexes that form spikes in the surface membrane of the virus. The immunodominant epitopes are hidden within the core of these complexes and therefore inaccessible to antibodies. Heavy glycosylation of gp120 also has the effect of inhibiting antibody binding.



The error-prone nature of HIV-1 reverse transcriptase activity during viral replication is also a key factor in viral escape from host immune responses. New mutations appear in approximately one-third of the virus produced, such that every possible point mutation in the HIV-1 genome arises on a daily basis. This generates hypervariable regions in gp120 that are more abundant on the exposed surface of gp41–gp120 complexes and contribute to viral escape from antibodies.



The continuous generation of mutant virus also underpins HIV-1 escape from antiviral CTL responses. In order to elicit these responses, HIV-1 antigens must be presented by MHC class I molecules on the surface of infected cells. In population studies, HIV-1 virus sequences have been found to have changed such that they cannot be presented by the most effective MHC class I molecules. In addition, components of HIV-1, particularly the accessory protein nef, reduce MHC class I expression, and the ability of HIV-1 to bind the receptor DC-SIGN on dendritic cells allows it to avoid the normal antigen processing pathway. All of these mechanisms serve to allow HIV-infected cells to go 'unnoticed'.


Innate immune defences are also undermined by HIV-1. IFN stimulates the expression of many genes that can 'restrict' the HIV-1 life cycle, but numerous mechanisms have been identified by which components of HIV-1 has evolved to avoid or degrade these defences. Finally, the ability for HIV-1 to establish latent infection, namely integrate into the host cell genome without replicating, is also an important immune evasion mechanism. During this time viral genes are not expressed and therefore cannot induce an immune response. Latent infections typically occur in long-lived memory CD4 T cells and tissue macrophages which form persistent and long-lived virus reservoirs.



HIV-1 Infection Immunology: Immunodeficiency


Progressive immunodeficiency and hence susceptibility to opportunistic infections or neoplasia is the hallmark of AIDS. The most widely used surrogate of immunodeficiency is destruction of naïve and memory CD4 T-cell populations.



Antigen naïve CD4 T cells recognize antigen presented with MHC class II by professional antigen-presenting cells. Clonal T-cell proliferation then follows, amplifying and regulating the wide spectrum of humoral and cellular immune responses. This process also leads to production of long-lived memory T cells with high affinity T-cell receptors for specific antigens that are primed to respond rapidly to subsequent antigenic challenge giving rise to the so-called recall antigen response.



During progressive HIV-1 infection and AIDS there is initially depletion of memory CD4 T cells followed by loss of naïve CD4 T cells. HIV-1 infection of CD4 T cells does cause cell lysis, but T-cell depletion seems to exceed the population apparently infected with virus. The mechanisms that contribute to T-cell loss are not yet fully understood, but the current paradigm suggests that HIV-1 replication occurs mainly within lymphoid tissues and causes immune activation. As discussed already, the consequent anti-viral immune responses partly control HIV-1 viral load, but since they do not eradicate the virus persistent viral replication and therefore persistent immune activation achieve a homeostatic set point. This corresponds to clinically asymptomatic state between primary HIV-1 infection and AIDS, which typically lasts 5–10 years, albeit with marked variability. This phase may progress rapidly (less than 1 year) in some patients or last longer than 10 years in 'long-term non-progressor' patients.



Persistent immune activation by HIV-1 may contribute to T-cell loss by two principle mechanisms. The early reduction in memory CD4 T cells is thought to be due to sequestration within activated lymphoid tissue. The subsequent loss of naïve T cells is attributed to a finite capacity for cellular activation and proliferation. In this model, lymphopenia results from persistent HIV-1 replication that stimulates cellular activation, and consequently activation-induced cell death or apoptosis, until the available naïve T cell pool is exhausted. This process is accelerated by a high rate of viral replication either as a result of poor anti-HIV immune responses, the generation of HIV-1 mutants that are able to evade host immunity and eventually by diminished ability of bone marrow progenitor cells to replenish the naïve T-cell pool. Another important mechanism for chronic immune activation and T-cell depletion focuses on HIV-1 replication in the gastrointestinal mucosa. This is thought to lead to early and substantial T-cell loss as a direct result of HIV-1 replication, and translocation of microbial products across the gut mucosal barrier that cause chronic immune activation and contribute further to systemic immune deficiency.



Importantly, HIV-1 does not simply induce anti-HIV responses but extensively dysregulated immune activation. This is illustrated by a variety of findings. T-cell proliferative responses to many stimuli become abnormal. Although quantitatively CD8 T-cell populations persist until very advanced HIV-1 disease, when all lymphocyte numbers fall, CD8 CTL function is impaired much earlier. B-cell hyperreactivity is also reflected in hypergammaglobulinaemia and bone marrow plasmacytosis, but is paradoxically associated with attenuated B-cell (antibody) responses to vaccination, suggesting impairment of specific B-cell function that mirrors the effects of HIV-1 on T cells.



Macrophage and dendritic cell dysfunction during HIV-1 infection are also recognized. These cells are involved in innate immune recognition of pathogens, early recruitment of host defences to the site of an infection and augmentation of adaptive immune responses. The effects of HIV-1 on these cells may therefore concurrently contribute to dysfunction of innate and adaptive immunity.



HIV-1 Infection Immunology: The Response To cART


Circulating CD4 T-cell counts rise following cART in most patients. This correlates strongly with the reduction in opportunistic infections in AIDS. The recovery of CD4 T cells is thought to result from reduction in HIV-driven dysregulated immune activation as viral replication is suppressed by cART. There is initially redistribution of lymph node-sequestered memory T cells, typically within 2 months. This is temporally associated with the development of immune reconstitution diseases in some patients with concurrent opportunistic infections. There is then gradual recovery of naïve T-cell populations that may continue over 2 years in patients who have had a very low CD4 T-cell nadir before starting cART. Recovery of CD4 T-cell activation markers, proliferation responses to recall antigens and T-cell receptor repertoires are also reported, but these seem to be incomplete. Limited studies also suggest only partial recovery of abnormal B-cell function after cART, and in some patients refractory reconstitution of the immune system has been associated with features that suggest persistent immune activation. A consensus view on the effect of cART on anti-HIV immune responses is not yet established, but most data suggest that HIV-specific responses decline as viral replication is suppressed. Rapid viral rebound during treatment interruptions confirm that the immune system is not able to control HIV replication after cART.



HIV-1 Infection Immunology: References