Pathogenesis of HIV Infection and AIDS
by Robert C. Mellors, M.D., Ph.D.
IV. Pathogenesis of HIV Infection and AIDS
Along with the cellular and humoral mechanisms of natural immunity, acquired immunity mediated by cytotoxic/suppressor CD8 T-cells and specific antibody synthesized as immunoglobulins by B cells protect the host from infection by myriads of microorganisms, such as bacteria, viruses, fungi, and parasites. Macrophages have a pivotal role in both natural and acquired immunity through phagocytic activity, processing and presenting antigenic peptides to responsive T-cells, and secretion of cytokines (IL-1, TNF, etc.). Dendritic cells found in peripheral lymph nodes, particularly germinal centers, and elsewhere have long cytoplasmic processes that localize and present antigens to responsive T-cells and B-cells. Natural killer cells also kill infected target cells directly or indirectly by antibody-dependent cellular cytotoxicity (ADCC).
CD4 T-cells have essential helper/inducer functions in both the cellular and humoral arms of specific immunity. By cell-to-cell contact and local release of regulatory cytokines (IL-2, IFN-gamma, etc.), antigen-responsive CD4 T-cells transmit activating signals to cytotoxic CD8 T-cells, antibody-producing B cells, and macrophages.
Immune deficiency in HIV infection
Persistent HIV infection with depletion of CD4 T-helper cells is central to the pathogenesis of HIV disease as manifested by immune deficiency, susceptibility to opportunistic infections, development of certain forms of cancer, and other AIDS-defining illnesses.
CD4 T-cell depletion. The depletion of CD4 T-cells in peripheral blood was the first immunological defect measured in patients with AIDS. CD4 T-cells also proved to be the main target of HIV infection both in vitro and in vivo. The CD4 glycoprotein on the surface of human CD4 T-cells and macrophages was found to be a high affinity receptor for HIV virions and envelope gp120. An essential coreceptor for HIV (either CCR5, new abbreviation R5, or CXCR4, abbreviation X4, both of the chemokine-receptor family) cooperates sequentially with CD4 to facilitate HIV entry into target cells.
The depletion of peripheral CD4 T-cells and progression to AIDS is driven by the HIV viral burden. HIV, both directly and indirectly, mediates the destruction and depletion of mature CD4 T-cells (which normally function as helpers to cytolytic CD8 T-cells) and also depletion of CD4 progenitor cells in bone marrow, thymus and peripheral lymphoid organs, resulting in failure of compensatory T-cell production and eventual collapse of the immune system (Mc Cune, J. M., Nature 410: 974-79, 2001).
Direct HIV-mediated cytopathic effects. Viral cytopathic effects were first observed in cultures of human peripheral blood CD4 T-cells and macrophages infected in vitro with HIV and comprise single-cell killing and cell-cell fusion with syncytium formation.
Evidence of increased cell-killing activity and syncytium induction are among the in vitro characteristics of HIV isolates recovered from individuals with advanced stages of HIV infection.
Additional postulated mechanisms of direct viral cytotoxicity include the accumulation of unintegrated viral DNA, which is cytotoxic, and the excessive production and accumulation of gp120 which mediates virus-cell and cell-cell fusion and is also directly cytotoxic.
HIV-specific immune responses.
- Cytotoxic CD8 T-cells -. Normally, CD8 T-cells recognize and, by contact, kill virus-expressing cells of the same MHC class 1 phenotype. Activated human CD8 T-cells are cytotoxic to HIV-infected CD4 cells with surface expression of env-, gag-, or pol-encoded proteins or cytotoxic to uninfected CD4 cells with surface-bound envelope proteins. In addition, CD8 T-cells can produce chemokines that suppress HIV replication in cultures of naturally or acutely infected CD4 T-cells, without necessarily killing them.
Most individuals infected with HIV display an early vigorous HIV-specific cellular and humoral immune response. HIV-specific cytotoxic CD8 T-cells have a significant, very likely pivotal, role in the control of HIV infection. The number and cytotoxic activity of circulating HIV-specific CD8 T-cells is inversely correlated with the plasma HIV RNA viral load in untreated patients at different stages of infection. (Ogg, G.S., et al., Science 279: 2103-2106, 1998).
- Neutralizing and enhancing antibodies -. The production of specific antibodies that bind to a virus and neutralize it is a function of B cells and the humoral immune response. In HIV infection, the viral envelope, particularly gp120 and often a commonly shared envelope epitope in the V3 loop, is the major target antigen for the host antibody response. While neutralizing antibodies may be detected against common laboratory strains of HIV, the antiviral titer against the patient's own virus is not consistently elevated, an enigma once suggesting viral envelope mutation but now also explainable by conformational (3-D) change in gp120 as it sequentially binds to CD4 and also to the coreceptor required for viral entry.
Furthermore, as HIV infection progresses in some patients, enhancing antibodies appear that bind to the viral envelope (without destroying it) and facilitate virus entry into macrophages and natural killer cells by way of IgGFc-receptors on the surface of these cells.
Antibodies to viral envelope proteins can also induce antibody-dependent cellular cytotoxicity mediated by natural killer cells and macrophages.
-Natural killer (NK) cells-. NK cells are large granular lymphoid cells that lack surface markers characteristic of T- or B-cells. NK cells have the natural capacity to kill virus-infected cells in the absence of prior sensitization and without MHC restriction. NK cells can kill target cells either by direct contact in the absence of antibody or by antibody-dependent cellular cytotoxicity (ADCC).
In ADCC, target cells bearing surface antigens, such as HIV gp120 or gp41, are killed when coated with specific antibody and bound via IgGFc -receptors to NK cells or macrophages.
NK cells and cytotoxic CD8 T-cells produce pore-forming molecules called "perforin" or "cytolysin" which have structural and functional similarity to C9 of the complement system and bind to cell surface membranes, forming transmembrane channels that lead to osmotic death of target cells.
Other postulated mechanisms
-Autoimmune mechanisms-. A large variety of autoantibodies ( to lymphocytes, platelets, neutrophils, erythrocytes, myelin, CD4, HLA, etc.) have been detected in the serum of patients with HIV infection.
The postulated autoimmune mechanisms include T-cell and B-cell dysregulation and molecular mimicry, namely, shared sequences or amino acid homology between HIV proteins and normal cellular components.
For example, MHC class II molecules (particularly HLA-DR and HLA-DQ), have some amino acid sequence homology with HIV envelope proteins, particularly gp41, and they share a common epitope. Autoantibodies to MHC class II proteins, presumably elicited by viral envelope proteins, are detected in the serum of patients with HIV infection. Such autoantibodies could interfere with the essential interaction between class II molecules and antigenic peptides required for antigen presentation by macrophages to helper/inducer CD4 T-cells, thus contributing further to the immune dysfunction in patients with HIV infection.
-Anergy.- HIV virions, gp120, and gp120-antigp120 complexes that bind to CD4 can interfere with the T-cell receptor for antigen and inhibit CD4 T-cell activation, a potential mechanism of immunological unresponsiveness in patients with HIV infection.
-Superantigens.- Some antigens ("superantigens") of bacterial origin (or retroviral origin in animals) have the capacity to bypass the normal routes of antigen processing and binding to the T-cell receptor for antigen and to stimulate large numbers of CD4 T-cells simultaneously, followed by deletion or immunological unresponsiveness of these cells. The clinical relevance of this postulated mechanism to human HIV infection is not presently known.
-Programmed cell death.- The natural process of programmed (non-random) cell death that occurs in the thymus (during the perinatal period of selection and deletion of self-responsive immature T cells) or in cells elsewhere during embryogenesis or normal cell turnover is called apoptosis (Gr. apo, away; ptosis, falling). This "physiological" process is characterized by distinct structural and biochemical changes, including cell and nuclear fragmentation (by a nuclear endonuclease), in the absence of pathological necrosis and inflammation.
Apoptosis can also be induced by pathological stimuli. For example, cultures of human CD4 T-cells either chronically or acutely infected with HIV die by apoptosis when activated by an antigen or mitogen. Further, the incubation of uninfected murine CD4 T-cells with HIV subunit gp120 alone, followed by activation of the T-cell receptor (TCR) for antigen induces apoptosis in these cells. The interpretation of these results is that gp120 binding and cross-linking of CD4 glycoprotein gives the first signal and that activation of the TCR by antigen (or potentially by superantigen) is the second and final signal for programmed cell death.
B cell dysfunction
B cells in patients with HIV infection also manifest many functional abnormalities, among them polyclonal activation, hypergammaglobulinemia, autoantibody production as noted previously, and impaired primary and secondary (memory) antibody responses to microorganisms, such as encapsulated bacterial antigens.
B cell abnormalities may be manifest at any, including an early, stage of HIV infection. Polyclonal B-cell activation is not unique to HIV infection and may occur in some other viral infections, such as EBV infection. A possible explanation for B cell hyperactivity in HIV infection, aside from defective T-cell regulation, is the reactivation of latent EBV infection or the induction and secretion of stimulatory cytokines (such as IL6) by activated or HIV-infected macrophages.
HIV infection of lymphoid organs
Recent studies, utilizing the polymerase chain reaction (PCR) to amplify HIV DNA and reverse transcriptase-initiated PCR (RT-PCR) to amplify HIV RNA, make it clear that lymphoid organs (lymph nodes, adenoids, tonsils) are the main anatomical sites of HIV infection in the early and clinically latent stages of infection. The frequency of HIV-infected cells in patients with early and latent stages of disease is much (~5 to 10 times) greater in lymphoid organs than in peripheral blood. By the in situ (single cell) PCR technique, the vast majority of HIV-infected CD4 T-cells (and macrophages) are latently infected, that is, contain HIV DNA without HIV RNA expression. As noted previously, latently infected CD4 cells can be activated by antigens (of other viruses and infectious agents), mitogens, certain cytokines and growth factors to initiate or increase HIV production.
By electron microscopic study, HIV virions are seen in the extracellular spaces along the extended processes of follicular dendritic cells (FDC) in the hyperplastic germinal centers of lymph nodes from patients with early and clinically latent stages of HIV infection. FDCs are apparently CD4 negative, non-phagocytic, antigen-trapping (and presenting) reticular cells that possess Fc- or C'-receptors for antibody- or complement-coated HIV virions. With loss of an effective immune response and clinical progression of HIV infection, the architecture of the lymph nodes, germinal centers, and FDC network becomes disrupted, apparently contributing to a rising level of plasma viremia.