Impact of CMV replication on the HIV-1 latent reservoir

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Replication competent HIV DNA that persists during antiretroviral therapy (ART) is the main impediment to HIV eradication. Levels of latent HIV DNA also predict the rate of CD4+ T-cell loss, time to AIDS, virologic failure of ART and end organ disease; therefore, reducing provial levels could have substantial clinical benefits. CMV replication in the genital tract is associated with higher levels of T-cell immune activation within both the genital compartment and peripheral blood. Because activated T-cells undergo extensive cell division and differentiation, proliferation of immune activated HIV-infected CD4+ T-cells is likely an important mechanism maintaining the size of the HIV latent reservoir. In this proposed project, our overarching goal is to determine if seminal CMV replication and related persistent immune activation impact the size of the HIV latent reservoir. Our objective is to understand the relationship(s) between HIV latency and CMV infection by investigating associations between: seminal CMV replication, immune activation status and changes in the T-cell subset profiles in blood and semen, and levels of T-cell proliferation and HIV transcription in blood with levels of cell-associated HIV DNA. We will evaluate these associations using innovative methods developed by our group and others, like multicolor flow cytometry and digital droplet (dd)PCR, which is an accurate, precise and sensitive technology to quantify small changes in HIV DNA copies in patients virologically suppressed with ART. These associations will be determined retrospectively using archived longitudinal paired samples of blood and semen collected from a well-characterized cohort of HIV-infected men (i.e. the San Diego Primary Infection Cohort) who started ART within 4 months of their infection and have sustained undetectable HIV RNA levels in blood plasma at week 48. The rationale of our proposal is that, once the relationship between CMV and the HIV reservoir is known, this connection could be targeted pharmacologically resulting in new approaches to reduce the latent HIV reservoir.