Page 40 - AIDSBK23C
P. 40

Page 40


               tumor necrosis factor (TNF).  Selenium supplementation may increase cellular antioxidant
               activity.  Selenium deficiency has been associated with increased mortality from HIV-1 infection
               in some studies.[220]
                       About 10% of persons infected with HIV-1 are nonprogressors, or "long survivors," who
               do not demonstrate a significant and progressive decline in immune function over more than 10
               years.  They do not appear to progress to AIDS in a manner similar to the majority of HIV-
               infected persons.  Findings in these "long survivors" include:  a stable CD4 lymphocyte count,
               negative plasma cultures for HIV-1, fewer HIV-infected cells, and a strong virus-inhibitory
               CD8+ T-lymphocyte response.  Differences in viral load do not appear to be associated with viral
               subtype, viral growth kinetics, or with the presence of neutralizing antibodies.[221]
                       In addition, by microscopic examination the lymph node architecture of "long survivors"
               with HIV infection is maintained without either the hyperplasia or the lymphocyte depletion that
               is common to progression to AIDS.  Though peripheral blood mononuclear cells contain
               detectable HIV-1 and viral replication continues in long survivors, their viral burden remains
               low.[222]  A strong host virus-specific CD4 lymphocyte response in these persons may also aid
               in controlling HIV viremia.[201]
                       The "elite controllers" of HIV suppress viremia below the limit of detection, <50
               copies/mL, even in the absence of antiretroviral therapy.  Though they have an initial viremia
               following primary infection with HIV, their immune systems quickly gain control.  They have a
               minimal CD4 lymphocyte decline, and their CD4 response is polyfunctional, without loss of
               specific CD4 clones.  Their cytolytic NK cells are preserved.  They have a more polyfunctional
               CD8 cytotoxic lymphocytic response, with strong granzyme-B-mediated cytolysis.[223]  Less
               than 1% of HIV-infected persons achieve such control, and are demographically heterogeneous
               with diverse racial backgrounds and modes of HIV transmission.[224]
                       There is evidence that genetic polymorphisms in the chemokine receptors present on cells
               susceptible to HIV infection may play a role in progression of AIDS.  At least in some persons
               infected with HIV, the presence of chemokine receptor variants, including the CCR5 delta32
               deletion or the CCR2B-64I mutation, have a favorable effect in slowing the progression of
               disease.  The CCR5 gene encodes the coreceptor for macrophage-tropic HIV-1, so reduced
               expression of CCR5 leads to reduced viral replication in macrophages.[225]  A lower density of
               CCR5 molecules on peripheral blood mononuclear cells has been shown to correlate with lower
               plasma HIV-1 RNA levels and reduced loss of CD4 cells over time.[226]  Patients homozygous
               for the chemokine receptor CX3CR1 progress to AIDS more rapidly than those with other
               genotypes.[227]
                       Genetic variations in HIV may play a role in disease progression.  The HIV-1 nef gene
               product activates production of T-cell attracting chemokines and contributes to the development
               HIV infection associated brain damage. Nef also downregulates CD4 and CCR5 expression and
               downregulates a subset of class I MHC molecules which contributes to viral immune evasion.
               Extracellular nef may facilitate the spread of T-cell-tropic HIV variants and mediate a switch in
               dominant replicating HIV strains from macrophage-tropic to T-cell-tropic viruses. Nef-deleted
               or nef-attenuated may be present in nonprogressors.[228]
                       Genetic variations in major histocompatibility (HLA) genes may determine HIV disease
               progression.  An HIV-1 envelope glycoprotein fragment mimics both HLA class 1C molecules
               and an immune regulatory epitope in the HLA DR beta chain, which furnishes peptides predicted
               to bind optimally to HLA class 1B alleles.  The HLA class I genes A29 and B22 are significantly
   35   36   37   38   39   40   41   42   43   44   45