The natural course of HIV-1 infection is widely variable with extremes of disease progression within 2 years or continuous asymptomatic infection for more than 15 years. Moreover, certain people are relatively resistant to HIV-1 infection despite high levels of sexual risk behaviour (high risk seronegatives, HRSN). In the majority of cases, the underlying mechanism responsible for the variable outcome of exposure to HIV-1 infection is not known. We hypothesize that host factors that either restrict or enable HIV-1 replication will be additional targets for therapeutic intervention. In the present study we will focus on the role of host factors in determining HIV-1 susceptibility using genome-wide single nucleotide polymorphism (SNP) analysis.
Participants of the Amsterdam Cohort Studies (ACS) have accurately documented levels of risk behaviour, moment of seroconversion for HIV antibodies and detailed follow up information on virological, immunological and clinical parameters, treatment history and disease course. Initially, we will perform SNP analyses on HRSN and the relevant control group, low risk seropositives (LRSP). In addition, CD4+ T cells from several of our HRSN participants have shown reduced susceptibility to HIV-1 in vitro. As host factors responsible for this reduced in vitro susceptibility may also be relevant in vivo, we will test in vitro HIV-1 susceptibility of blood cells from family members of these HRSN and LRSP to extend SNP analysis to these family members to increase the power of our analysis. Altogether, this will provide a genome-wide analysis of host polymorphisms that could be relevant to HIV infection.
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