Kaposi sarcoma (KS), the most common HIV-associated malignancy worldwide, is attributable to infection with human herpesvirus 8 (HHV-8). In populations in the US and Africa with high prevalence of HIV infection, HHV-8 co-infection is extremely common. The ramifications of HIV and HHV-8 co-infection for the natural history of HIV and HHV-8 associated diseases are unknown. However, it is clear that HIV increases the incidence and severity of KS, and our preliminary data find that HHV-8 infection may also exacerbate the progression of HIV disease. Highly active antiretroviral therapy (HAART) reduces the incidence and severity of KS in the US, but may not be as effective in Africa where the burden of HHV-8 disease is substantially higher and immune reconstitution inflammatory syndrome (IRIS) commonly leads to a worsening of HHV-8-associated disease. Based on previous and ongoing research, our group has developed a conceptual model which posits that: A) among individuals co-infected with HIV and HHV-8, each virus acts synergistically to enhance the other's replication;B) the use of HAART reduces HHV-8 replication in a manner which is both dependent and independent of its effect on HIV replication;C) persons with HHV-8 infection are divided between those with frequent replication in the peripheral blood and at mucosal sites and those without;and D) persistent HHV-8 replication may limit the efficacy of HAART in suppressing HIV replication We propose a prospective cohort study of 350 HIV/HHV-8 co-infected Ugandans initiating HAART to evaluate the following Specific Aims: (1) Determine whether the clinical and virologic manifestations of HIV infection at the time of HAART initiation, and in the 2 years following, impact the suppression of HHV-8 mucosal and peripheral blood replication;(2) Determine whether the virologic characteristics of HHV-8 infection at the time of HAART initiation, and in the 2 years following, impact the suppression of HIV at mucosal and peripheral blood sites;(3) Characterize the frequency and correlates of HHV-8-associated IRIS.

Public Health Relevance

This proposal seeks to understand how HIV and human herpesvirus 8 co-infection may impact the natural history of both HIV and HHV-8 associated disease. Knowledge gained from this proposal may lead to improved strategies for the use of highly active antiretroviral therapy among the majority of HIV-infected individuals worldwide who are HIV and HHV-8 co-infected, better preventative measures and treatments for HIV- associated cancers, and new strategies for increasing the efficacy of HAART in preventing HIV disease progression and transmission.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138165-03
Application #
8278460
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Dominguez, Geraldina
Project Start
2010-09-20
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$297,837
Indirect Cost
$85,726
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Gantt, Soren; Cattamanchi, Ashok; Krantz, Elizabeth et al. (2014) Reduced human herpesvirus-8 oropharyngeal shedding associated with protease inhibitor-based antiretroviral therapy. J Clin Virol 60:127-32
Gantt, Soren; Casper, Corey; Ambinder, Richard F (2013) Insights into the broad cellular effects of nelfinavir and the HIV protease inhibitors supporting their role in cancer treatment and prevention. Curr Opin Oncol 25:495-502
Gantt, Soren; Carlsson, Jacquelyn; Ikoma, Minako et al. (2011) The HIV protease inhibitor nelfinavir inhibits Kaposi's sarcoma-associated herpesvirus replication in vitro. Antimicrob Agents Chemother 55:2696-703
Gantt, Soren; Casper, Corey (2011) Human herpesvirus 8-associated neoplasms: the roles of viral replication and antiviral treatment. Curr Opin Infect Dis 24:295-301