To analyze the correlation between phenotype/genotype to selected antiretroviral agents and short-term change in viral load upon discontinuation of a single antiretroviral agent from a failing regimen, one drug in a failing multidrug regimen is withdrawn for a limited period of time, and then restored. By monitoring changes in both viremia and genotype (by the limiting dilution assay), we can discern whether the drug was contributing to partial suppression of virus, and also determine which mutations are associated with resistance to that drug, and their effect on both replication of the virus and resistance to the drug. In collaboration with Dr. Vinay Pathak (National Cancer Institute), we have begun to analyze the entire RT sequence to determine whether additional changes in the RNAse H portion of RT are associated with partial drug suppression. With Dr. Anuradha Ganesan (Henry M. Jackson Foundation), we have initiated a new site for this protocol at the National Naval Medical Center. The need for new antiviral agents continues, and identification of cellular pathways participating in HIV-1 maturation by Dr. Eric Freed in the HIV Drug Resistance Program (DRP) and others have suggested novel strategies to inhibit virus replication by disrupting host-viral interactions required for virion maturation. Specifically, we are studying the cholesterol-lowering agent atorvastatin, which reduces viral yield and infectivity in vitro by reducing cholesterol in lipid rafts required for HIV-1 maturation. Previous observations by our Host-Virus Interaction Branch (HVIB) and others have yielded conflicting evidence on the potential antiviral benefit of statin therapy. In collaboration with the National Naval Medical Centers in Bethesda and San Diego (Drs. Anuradha Ganesan and Nancy Crum-Clanfione) and with the NIH Clinical Center (Dr. Henry Masur), the HVIB is conducting the first randomized, placebo-controlled trial of atorvastatin in HIV-1 infection (Protocol 06-I-0197). This study includes a detailed analysis of host and viral genetics as well as extensive immunophenotyping; as a result, we will not only determine the overall utility of the statin approach in inhibiting HIV-1 replication, but also investigate the genetic correlates associated with success or failure of this approach and identify immune effects of statin therapy. The comprehensive approach will serve as a model to extend to additional agents with potential antiviral activity. Several clinical groups at NIH (Drs. Irini Sereti and Joann Mican, NIAID) have engaged DRP investigators to collaborate in analyzing resistance profiles arising in patients on standard and experimental therapy. In addition, the HVIB serves as a primary resource for interpretation of genotypic and phenotypic information for a number of protocols, notably Protocol 95-I-0072 (Joann Mican, NIAID Principal Investigator; Frank Maldarelli, DRP, Associate Investigator), used in training of infectious disease fellows, and for local referral of difficult cases. These interactions support mentoring of trainees and also result in new and clinically relevant information regarding HIV and antiviral therapy. In collaboration with NIAID (Drs. Joann Mican and Alice Pau), HVIB investigators recently characterized a previously unrecognized interaction between the antiretroviral ritonavir and local epidural hydrocortisone preparations. In addition, with Drs. Joann Mican and H. Clifford Lane (NIAID), we are in the process of characterizing a new drug insertion mutation in subtype C reverse transcriptase with novel phenotypic resistance properties. A direct clinical outcome of the expertise gained in these studies has been in evaluating cases of occupational exposure to HIV that have occurred in NIH clinical and veterinary settings. Exposure to drug-resistant virus as well as novel HIV and recombinant SHIV experimental viruses requires detailed considerations for post- exposure prophylaxis (PEP). The HVIB has been consulted by Occupational Medical Services for exposures occurring at NIH and has been instrumental in assisting in the construction of non-standard PEP regimens designed for specific exposures. [Corresponds to Project 4 in the April 2007 site visit report of the Host-Virus Interaction Branch, HIV Drug Resistance Program]
