Host Genetic Factors in the HIV Virus Life-Cycle and HIV Disease Progression

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DESCRIPTION (provided by applicant): In the absence of therapy, most humans infected with HIV-1 progress to AIDS and eventually die. However, there is distinct variation in the rate and characteristics of that disease progression ranging from rapid progression over months to lack of progression for years. Increasingly, host genetic elements have been found to modify HIV disease progression. But these genetic factors have not been well studied in African cohorts despite the fact that the HIV burden is greatest in Africa. Studies have evaluated the role of variants in genes associated with HIV cell entry (such as the CCR5 A32 mutation). However, host genes are now known that mediate other HIV life cycle stages including viral integration, capsid formation and ihtracellular trafficking and budding. The impact of these these "HIV life cycle host genes" on HIV disease progression has not been well studied, particularly in African populations. We are in a unique position-to use specimens being collected in a clinical trial of HIV suppression in Africa to further study the role of host genetic factors in HIV disease progression in Africa. The Partners in Prevention Clinical Trial (Partners Study) is designed to assess the effect of genital herpes suppression with acyclovir in reducing HIV transmission. To accomplish this, 3000 HIV-discordant couples, in which the HIV- infected partner is co-infected with genital herpes (HSV-2) and CD4>250 cells/mm3, are being enrolled in diverse populations in Eastern and Southern Africa. Herpes suppression with daily acyclovir will be provided to the HIV-infected partner and both partners followed quarterly for 18-24 months. Whole blood specimens are being stored with informed consent for future host genetic studies on HIV disease. This large study presents a unique opportunity to evaluate genetic factors modifying HIV disease in Africans. Here we propose to use specimens from the Partners Study to evaluate host polymorphisms in genes that interact with HIV during life cycle stages including cell entry, nuclear targeting, capsid formation, cellular trafficking and budding. Our Specific Aims are: 1) Determine the frequency of specific genetic variants in the Partners study populations and in so doing, assess the capacity of the HapMap and other existing public SNP discovery databases to evaluate genetic variants across diverse African populations. 2) Apply multivariable linear regression and other statistical methods to the genetic data collected in Specific Aim 1 to evaluate the association of these genetic variants with disease progression as measured by viral load at enrollment, viral load change over follow-up and time to reach CD4<200 cells/mm3.