An understanding of HIV life cycle is necessary to appreciate the induction of immunosuppression. The hallmark of HIV-1 infection is progressive depletion of the CD4 helper-inducer subset of lymphocytes. Because of the central role of these cells in immunologic functioning, the clinical disease manifestations of immunosuppression and susceptibility to opportunistic infections and neoplasms are not surprising. The immunologic deficits associated with HIV-1 infection are widespread and involve numerous interdependent effector arms of the immune system, including both cellular and humoral elements.
Direct Immunosuppressive Properties of Viral Products
Protein products of a number of retroviruses have been shown to have direct immunosuppressive properties independent of viral infection. A synthetic peptide corresponding to a highly conserved region in the HIV-1 envelope gp41 transmembrane protein has been demonstrated in vitro to inhibit lymphocyte proliferative responses to mitogenic or antigenic stimuli. This region is analogous to a highly conserved immunosuppressive protein of human T-lymphotrophic virus I (HTLV-I), and similar inhibitory transmembrane proteins have been identified in other animal retroviral infections, such as feline leukemia virus (FeLV). Whether such a phenomenon contributes to the global immunosuppression seen in HIV-infected individuals has not been determined, but the possibility that HIV-1 proteins may be immunosuppressive has raised concerns about inclusion of such sequences in potential HIV vaccine candidates.
T Lymphocyte Abnormalities
Lymphocyte abnormalities associated with HIV-1 infection can be classified as both quantitative and qualitative. Qualitative deficiencies become apparent soon after infection and before CD4 depletion is evident, and may be related to virus-related functional defects in the helper-inducer subset of lymphocytes. Studies using purified subpopulations of lymphocytes from AIDS patients have demonstrated a selective defect in soluble antigen (e.g., tetanus toxoid) recognition, although these cells are still able to respond to mitogen (e.g., phytohemagglutinin). In other words, the weapon is loaded, but only mitogens and not antigens cause the trigger to be pulled. These studies also indicate that the central defect is lack of helper cell function, rather than an overabundance of suppressor cell activity. Other lymphocyte abnormalities observed with HIV-1 infection include decreased lymphokine production, decreased expression of interleukin-2 (IL-2) receptors, decreased alloreactivity, and decreased ability to provide help to B cells. The functional T lymphocyte abnormalities are also likely to contribute to the loss of delayed-type hypersensitivity reactions that become more prevalent as disease progresses.
The quantitative abnormality of T lymphocytes is the result of progressive depletion of the CD4+ helper T lymphocyte population, which begins soon after primary infection. This downhill trend continues until the normal levels of 800 to 1200 CD4 cells per cubic millimeter drop below 50 cells per cubic millimeter and often lower than 10 cells per cubic millimeter in the later stages of disease. CD4 cell depletion cannot be attributed solely to direct cytotoxic effects of virus infection, because only a minority of helper cells are actually infected, even in later stages of illness. Other factors potentially contributing CD4 depletion include (1) syncytia formation, in which a single infected cell fuses via its surface gp120 with the CD4 molecule on uninfected cells, forming multinucleated giant cells; (2) “innocent bystander” destruction of uninfected CD4 cells that have bound free gp 120 to the CD4 molecule, rendering them susceptible to immune attack; (3) HIV-1 infection of stem cells or HIV-1-induced thymic depletion, resulting in decreased helper cell production; (4) autoimmune mechanisms, whereby cross-reactive antibodies or cellular immune responses to the virus result in killing of uninfected CD4 cells; (5) superantigen effects, in which a viral protein would be hypothesized to lead to stimulation and ultimately depletion of CD4 lymphocytes bearing a specific T cell receptor; and (6) apoptosis, whereby virus or viral products would induce programmed cell death (PCD). Whatever the mechanisms of the CD4 cell depletion, the resultant consequence to immune function is so profound that total CD4 number is an important prognosticator of disease progression. The risk of certain opportunistic infections increases significantly when the total CD4 cell number is lower than 200 per cubic millimeter, which is why routine prophylaxis against Pneumocystis carinii pneumonia (PCP) is instituted at this stage. At levels below 50 to 100 cells per cubic millimeter, the risk for other complications, such as disseminated mycobacterium avium or cytomegalovirus (CMV) infections, increases dramatically.
Lymphocytes also represent a very important reservoir of persistent infection. It is estimated that approximately one million CD4 lymphocytes in an infected person contain stably integrated provirus that is in a latent state but fully capable of replication when the cell is activated. Because these cells do not make viral proteins until they are activated, they are hidden from immune attack and are not susceptible to current antiviral drugs, and thus represent a substantial hurdle for ultimate eradication of the virus.
B Lymphocyte Abnormalities
As with T lymphocyte abnormalities in HIV-1 infection, the B lymphocyte abnormalities are both quantitative and qualitative. Most characteristic, particularly in the early stages of infection, is intense polyclonal activation of B cells, evidenced clinically by elevated levels of immunoglobulins G and A, the presence of circulating immune complexes, and an increased number of peripheral blood B lymphocytes that secrete immunoglobulin spontaneously. These B cell abnormalities are unlikely to be a direct consequence of HIV-1 infection of B cells. Whereas B cells can express low levels of CD4 and have been infected in vitro, there are no conclusive data indicating that these cells became infected in vivo. Rather, the virus itself or viral proteins appear to directly interact with and stimulate uninfected cells. Other potential contributors to this polyclonal activation include concurrent viral infections. For example, CMV and Epstein-Barr virus (EBV) infection occur with greatly increased frequency in HIV-1-infected individuals and can lead to B cell hyperactivity.
Functional abnormalities of B cells consist particularly of impaired antibody responses to antigenic stimuli, and impaired T cell helper function also may contribute to this problem. These impaired antibody responses may account for the increase in pyogenic infections seen in advanced HIV-1 infection. In addition, decreased antibody responsiveness to vaccination against viruses such as influenza A and hepatitis B is also characteristic of late-stage HIV infection.
It has been clearly demonstrated that HIV-1 also infects cells of the monocyte/macrophage lineage, which express CD4 as well as the coreceptor molecule CCR5. Infection and high-level replication of HIV-1 have also been demonstrated in monocyte/macrophage progenitor cells of normal bone marrow and may contribute to the pancytopenia seen with HIV infection. Unlike CD4 lymphocytes, however, macrophages appear to be relatively resistant to the cytopathic effects of HIV infection and may therefore constitute a persistent reservoir of infection. Macrophages may also play an important role in viral dissemination within the infected individual, in particular carrying virus across the blood-brain barrier to the central nervous system (CNS).
At least in part as a consequence of HIV infection, a number of monocyte/macrophage abnormalities have been detected in HIV-seropositive persons. The ability of monocyte/macrophages to act as antigen-presenting cells is impaired, particularly in later stages of illness. Some defects in these cells in AIDS patients may be a consequence of chronic in vivo activation, such as increased IL-2 receptor expression, IL-1 secretion, and increased chemotactic ligand receptor expression. The reasons for this chronic activation likely are multifactorial and may relate to exposure to viral proteins or lymphokines or to direct effects of HIV infection. These abnormalities may have immunopathogenic consequences, because defects in the ability to present antigens ultimately could impair the ability to sustain an immune response against HIV-1 or other pathogens.
In the brain, cells of the macrophage lineage appear to be the major cell type infected with HIV-1 and directly or indirectly may contribute to the CNS dysfunction observed in this disease. In the lung, infected alveolar macrophages may stimulate HIV-1-specific immune responses, the byproducts of which have been postulated to contribute to the observed alveolitis. Deficient CD4 T helper cell function also indirectly may contribute to the observed defects in monocyte/macrophages, because a minority of monocyte/macrophages appear to be actually productively infected in vivo.
Natural Killer Cell Abnormalities
Natural killer (NK) cells are thought to be an important component of immunosurveillance against virus-infected cells, allogeneic cells, and tumor cells. NK cells typically are large granular lymphocytes that recognize foreign antigens on cells, resulting in activation of lytic machinery. NK cells are phenotypically and numerically normal in AIDS patients, but they are functionally defective. This may relate in part to an observed defect in the trigger mechanism necessary to deliver the lethal blow to a target cell. In addition, defective lymphokine production in HIV-1-infected persons may also contribute to NK cell dysfunction. However, adding IL-2 to these cells in vitro only partially restores NK function.
Autoimmune phenomena are also part of the immunologic derangement in HIV-1 infection and may also contribute to the disease manifestations seen clinically. When sensitive assays are used, circulating immune complexes can be detected in the majority of HIV-infected individuals. These may help to explain the occurrence of HIV-1-related arthralgias, myalgias, renal disease, and vasculitis.
Revision date: July 5, 2011
Last revised: by Janet A. Staessen, MD, PhD