Quantification of HIV-1 Reservoirs in the Gut

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DESCRIPTION (provided by applicant): My research background includes: 1) investigating the transcriptional control of the gene c-kit; 2) investigating whether the viral transcription factor Tat contributes to latent infection with HIV-1; and 3) investigating HIV levels and immune parameters within different parts of the gut. In applying for the NIH Career Development Award (CDA), I hope to acquire the experience, skills, and knowledge necessary to become an independent faculty investigator who uses patient-driven research to better understand the obstacles to eradication of HIV. This CDA will enable me to obtain additional training in several key areas that will facilitate my transition to an independent translational researcher. The research environment will include UCSF and three affiliated institutions: San Francisco General Hospital, the San Francisco VA, and the Gladstone Institute. These institutions are nationally known for clinical care, training, and research in HIV. This study seeks to improve understanding of how and why HIV persists on antiretroviral therapy (ART) by investigating whether there is ongoing replication in the gut, whether the gut is a major reservoir of latently-infected CD4+ T cells, and whether new antiretrovirals or anti- latency therapies can impact ongoing replication and/or latent infection in the gut. The specific aims are: 1) to compare HIV levels and immune parameters in different regions and cell types within the gut; 2) to assess for ongoing replication in the gut by measuring the effect of therapy intensification on levels of HIV, immune markers, and markers of abnormal gut barrier function; and 3) to assess the size of the gut latent reservoir, investigate mechanisms of latency in the gut, and assess the response of gut cells and tissues to anti-latency therapies. Study part 1 is a prospective, longitudinal pilot study in which participants will have baseline upper and lower endoscopy with biopsies from 4 regions followed by 12 weeks of intensification (with raltegravir +/- a second agent) and repeat endoscopies. Part 2 of the study will involve endoscopy with more intensive sampling from one gut site (part 2A) as well as unused tissue from HIV+ patients who are undergoing abdominal surgery for other reasons (2B). These biopsies and tissues will be used to identify the cell populations with the most HIV DNA and RNA, to establish culture systems to measure inducible and/or replication-competent HIV in the gut, to investigate mechanisms of latency in the gut, and to test the effect of different anti-latency therapies. The knowledge thus gained may ultimately contribute to new and improved therapies aimed at eradication or lifelong coexistence with HIV. Though antiviral medicines have revolutionized the lives of those with HIV, these therapies are expensive, require lifelong administration and monitoring, have risk of side effects and toxicities, do not eradicate HIV, do not completely reverse the immune deficits of HIV, and are difficult to provide to everybody with HIV. Thus, it seems imperative to explore new and different therapies for HIV, especially those that can possibly lead to eradication or improved tolerance of lifelong HIV infection. This study seeks to improve understanding of how and why HIV persists on therapy by investigating whether there is persistent viral replication in the gut, whether the gut is a major reservoir of latently-infected cells, and whether new therapies can impact persistent replication and/or latent infection in the gut.