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 Robert M. Grant, M.D., M.P.H.
Betty Jean and Hiro Ogawa Endowed Investigator
Gladstone Institute of Virology and Immunology
Associate Professor of Medicine
University of California, San Francisco
Email: robert.grant@ucsf.edu
Phone: 415-734-4810
Administrative Assistant: Malu Robles, BS
Email: malu.robles@gladstone.ucsf.edu
Phone: 415-734-4813
Fax: 415-355-0855
Areas of Investigation
An emerging area of focus for the laboratory is the evaluation of Pre-Exposure Prophylaxis (or PrEP) for prevention of HIV transmission. (See PrEP Policy Forum in Science). This strategy involves use of antiviral agents to block transmission of HIV-1 to highly exposed persons. The research includes a clinical trial in Peru, a setting where HIV-1 continues to spread despite widespread access to condoms, counseling, and STD management. Collaborators at Asociación Civil Impacta Salud y Educación (or Impacta). Impacta is an organization having strong ties to the community and an outstanding record for high quality clinical research. Our research on PrEP also involves detailed virological and immunological research to determine if exposure to antiviral agents early in the course of infection has durable benefits due to lower viral load and preservation of antiviral immune responses.
We are also interested in HIV-1 superinfection, where persons already infected with HIV-1 acquire additional strains of the virus. Superinfection may allow viruses to spread which are more drug resistant or more virulent. This is a significant concern for people with HIV infection, especially those in relationships with other infected persons. We also are interested in mechanisms that may block superinfection in some persons, as knowledge of these mechanisms may guide vaccine development. (See Positive Partners)
In addition, we investigate consequences of molecular evolution, including (1) the fitness of drug-resistant HIV-1 for replication, virulence, and transmission; (2) selection pressures bearing on HIV-1 populations in tissues; and (3) nonpathogenic simian immunodeficiency virus (SIV) infection in natural host species. These topics are studied in close coordination with the AIDS Research Institute-UCSF Laboratory of Clinical Virology, for which Dr. Grant is the Medical Director. Our long term goal is to understand the viral and host characterstics that underlie patterns of epidemic spread of HIV-1 in human communities.Significance
Evolution is a basic characteristic of life and has important implications for medicine. Genetic variations in host susceptibility and microbial replication capacity, virulence, and drug sensitivity typically determine who develops disease and who remains healthy. As such, molecular evolution is the basis of epidemiology, the science that studies the determinants of disease distribution in populations. Approaches
We study HIV-1 variants that are derived from subjects in well defined epidemiological settings. For example, pairs of drug resistant and susceptible viruses, or viral gene segments, derived from subjects before and after therapy are compared with respect to replication capacity, fitness, and cytopathicity. Determinants of viral transmission are identified using viruses from recently infected persons and their partners.
 Contributions
We identified the first case of sexual transmission of HIV-1 resistant to multiple classes of antiretroviral therapy. We later found that transmitted drug resistance is becoming more common in San Francisco, which has served as a sentinel site for trends around the world. We have also found that drug resistant viremia is often associated with persistent partial immunological and virological responses to therapy. These partial responses were found to be dependent on continued exposure to drugs, which continue to have antiviral activity and select for viral variants with diminished replication capacity. These multi-drug resistant HIV-1 variants are cytopathic for activated peripheral blood mononuclear cell cultures and lymphoid histocultures, but are associated with low viral load in nonlymphoid tissue compartments, like cerebrospinal fluid that bathes the brain. In a separate line of research, we discovered that sooty mangabeys, a natural host for simian immunodeficiency virus, tolerate high level viremia for many years with no evidence of progressive or clinical immunodeficiency. Virus and host coevolution leading to nonpathogenic infection is under investigation. Like humans, sooty mangabeys can have a null allele of CCR5, providing an example of parallel evolution within two lentiviral host species. Some questions addressed in ongoing studies - Can daily oral use of generally safe antiviral agents serve to prevent acquisition of HIV infection?
- Does exposure to antiviral agents early in the course of HIV-1 infection attenuate the course of infection by sparing anti-viral immune responses and lowering viral load?
- Are some types of drug resistant HIV-1 more transmissible than others?
- Does drug resistance affect virulence and host tissue range?
- What is the frequency of HIV-1 superinfection?
- Can superinfection spread HIV-1 that is more transmissible, drug resistant, or virulent?
- How does the sex of the host affect viral evolution?
- What viral characteristics are important for transmission between human hosts?
- What viral and host proteins affect viral mutagenesis?
Selected Publications
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