Pre-Exposure Prophylaxis for prevention of HIV transmission

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Areas of Investigation
An emerging area of focus for the laboratory is the evaluation of Pre-Exposure Prophylaxis (PrEP) for HIV prevention. (See Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men). PrEP involves the use of antiviral agents to block transmission of HIV-1 to highly exposed persons. The research includes a global clinical trial with sites in Brazil, Ecuador, Peru, South Africa, Thailand and the United States, countries where HIV-1 continues to spread despite access to condoms, counseling, and STD management.

iPrEx was the first clinical trial to demonstrate that the use of an antiretroviral drug (ARV) combination of embtricitabine 200 mg. and tenofovir 300 mg., commercially known as Truvada®, offered 44% additional protection against HIV infection in gay men, transgender women and other men who have sex with men and more than 90% if taken consistently enough to have detectable drug levels in blood.

On the day of the announcement of the iPrEx results in November of 2010, President Barak Obama congratulated the study team for the findings. The results were considered as the No. 1 medical breakthrough of 2010 by Time magazine, and Science included the study as one of the breakthroughs of the year 2010. The Lancet considered the iPrEx results article, published in the New England Journal of Medicine, as the six papers most likely to influence practice and research. 

In early 2011 the Centers for Disease Control and Prevention (CDC) released Interim Guidance: Preexposure Prophylaxis for the Prevention of HIV Infection in Men Who Have Sex with Men.  In July of 2012, the Food and Drug Administration (FDA) approved the use of Truvada for the prevention of HIV infection in sexually active adults based on iPrEx results and the Partners PrEP study conducted by the University of Washington.    

Another area of interest is the analyses and understanding of HIV host interactions related to HIV chemoprophylaxis including the success or failure of PrEP, drug resistance, detection of drug levels and immune responses.

HIV-1 superinfection where persons already infected with HIV-1 acquire additional strains of the virus is of particular interest in our laboratory. Superinfection may allow viruses to spread some of 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.

In addition, we investigate consequences of molecular evolution, including (1) the fitness of drug-resistant HIV-1 for replication, virulence, and transmission and (2) selection pressures bearing on HIV-1 populations in tissues. 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 characteristics 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

  1. Can daily oral use of generally safe antiviral agents serve to prevent acquisition of HIV infection?
  2. 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?
  3. Are some types of drug resistant HIV-1 more transmissible than others?
  4. Does drug resistance affect virulence and host tissue range?
  5. What is the frequency of HIV-1 superinfection?
  6. Can superinfection spread HIV-1 that is more transmissible, drug resistant, or virulent?
  7. How does the sex of the host affect viral evolution?
  8. What viral characteristics are important for transmission between human hosts?
  9. What viral and host proteins affect viral mutagenesis?