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