The role of CD4 polymorphism on HIV infection and disease progression.

摘要

Since the first reported cases of AIDS in 1981, to date there is no vaccine available to prevent HIV infections and the anti-retroviral drugs available can only prolong the lives of those infected. Sub-Saharan Africa, with about 10% of the global population, harbors over 65% of all HIV infected individuals. Many factors including host genetics have been documented that helped in the spread of HIV in this region. A Single Nucleotide Polymorphism (SNP) on CD4 found at higher prevalence among people of African descent is a possible host genetic factor that could explain the dramatic spread of HIV in this region. We hypothesize that a SNP encoding an amino acid change in the third domain of CD4-Trp240(868T) may alter its tertiary structure thus changing its functions with respect to HIV-1 infection or signal transduction. We investigated these possibilities by testing the susceptibility of a T-cell line, A2.01, transfected to express similar levels of either phenotype (A2.01/868T) or wild-type CD4(A2.01/868C), to both laboratory-adapted HIV viruses and clinical HIV isolates. We also investigated whether CD4-specific signal transduction is altered in cells with A2.01/868T cells by cross-linking CD4 with anti-CD4 monoclonal antibody. A2.01/868T cells were found to be more susceptible to infection with both X4-tropic virus and clinical HIV isolates relative to cells that express wild-type CD4. Subsequent infection of A2.01/868T and A2.01/868C cells with a CD4-independent virus showed no difference in the cell lines ability to support HIV-1 replication. This demonstrates that differences in the infections observed when using a CD4-dependent virus are due to the CD4 isotype and not the cell lines' ability to support HIV-1 replication. Although the CD4-Trp240(868T) was found to bind gp120 of HIV-1 with low affinity, cross-linking of these cells with anti-CD4 demonstrated that signal transduction was enhanced, immune activation markers were elevated and apoptosis occurred at a higher rate in these cells than those with wild-type CD4 phenotype. This implies that the ability of cells expressing CD4-Trp240(868T) to become activated more easily could be a factor in the increased susceptibility to HIV-1 infection observed. In conclusion, in addition to confirming that CD4 SNP is a risk factor with respect to HIV infection and disease progression, this study has provided insight into the molecular basis for these risk factors. Those who have this polymorphism have CD4+T cells that have increased susceptibility to HIV-1 and upon infection they loss these cells more rapidly by either apoptosis or activation induced cell death.;There are three fundamental significant findings from this study. First, CD4 polymorphism is highest among the Africans, the same population with the highest HIV-1 prevalence globally. This study together with the previous epidemiology studies, confirm that CD4 SNP is one of the host factors that could have contributed to the rapid spread of HIV in Sub-Saharan Africa. Second, given that there is no effective vaccine for prevention of HIV-1 infection, there is need to improve on the currently available anti-retroviral drugs. The finding that gp120 of HIV binds to CD4-Trp240(868T) with low affinity is an important observation and could be used to help in designing better anti-retroviral drugs especially the fusion inhibitors. Lastly, the finding that individuals with CD4 SNP progress rapidly to AIDS due to either apoptosis or activation induced cell death should be used to investigate further how these mechanisms could be inhibited with the view of slowing disease progression.