UCSF-GIVI Center for AIDS Research

Natural killer (NK) cells have traditionally been considered members of the innate immune system. Recently, in a mouse model of cytomegalovirus, our lab has demonstrated that NK cells undergo clonal expansion during acute viral infection, the population contracts when virus is controlled, but remarkably infection induces a population of "memory" NK cells. These cells are long-lived, respond more robustly when re-challenged, and provide enhanced host protection against re-infection. We hypothesize that human NK cells that have been clonally expanded by pathogen exposure can be identified by the CD57 marker and that NK cell that have responded to human cytomegalovirus (HCMV) will preferentially express the activating NKG2C receptor. We propose experiments to define the functional properties and transcriptional signature of these human NK cell populations to obtain preliminary results to demonstrate feasibility for a major NIH grant on this subject. If "memory" NK cells do exist in humans, these may be important in the control of chronic infections such as HIV, HCMV, or hepatitis C, and provide new therapeutic opportunities for vaccination of NK cells against pathogens. Back to top

Kaposi's sarcoma-associated herpesvirus (KSHV) is the viral etiologic agent of Kaposi's sarcoma (KS). In sub-Saharan Africa, the catastrophic intersection between underlying endemic infection with KSHV and the HIV epidemic has resulted in KS becoming the most common malignancy among adults in many countries and a growing cause of cancer in children. In areas where KS is most common in Africa ("the KS belt" in equatorial East and Central Africa), KSHV is primarily acquired in childhood, but little is known about biological determinants of KSHV infection in children or manifestations of primary infection. Data are especially limited regarding whether HIV influences susceptibility to KSHV infection or modifies the initial disease course. The proposed research will examine interactions between HIV and KSHV in Ugandan children by conducting one of the first longitudinal examinations of KSHV infection in African children. Our specific aims are to (1) compare KSHV prevalence between HIV-infected and HIV-uninfected children; (2) ascertain the role of HIV infection in acquiring new KSHV infection among African children; and (3) determine clinical and laboratory manifestations of primary KSHV infection in African children and determine whether HIV infection modifies these manifestations. To achieve these aims, we will employ a cost-efficient approach of using existing biological samples and data collected in two previously assembled cohorts of HIV-infected and -uninfected Ugandan children. This study will provide the requisite data for an NIH R01 proposal to support the dedicated investigation of the behavioral and environmental determinants of KSHV infection in childhood in sub-Saharan Africa. Back to top

Research on the role of migration in the spread of HIV/AIDS has almost exclusively focused on male labor migration patterns, finding migration to be a risk factor for men and their non-migrant partners, yet neglecting to measure the HIV risks of migration for women. Moreover, the very manner in which migration is conventionally studied is shaped by the paradigm of male labor migration, and thus fails to capture the complexity of women's mobility in sub-Saharan Africa today. Yet, prior research suggests that women are significantly involved in migration flows in sub-Saharan Africa, where their rates of HIV infection exceed those of men. This pilot study thus addresses a neglected area of HIV prevention research: the HIV risks associated with migration for women. The objectives of this ethnographic study are to: 1) characterize and compare the types of migration and mobility among women and men in western Kenya; 2) characterize the spatial and social features of the common destinations of female migrants; and 3) identify the features of women's migration experience which may render it particularly hazardous vis-à-vis their HIV infection risk. We will carry out participant observation in the "high HIV risk environments" of selected common migration destinations in Nyanza Province, and in-depth semi-structured interviews female and male migrants systematically selected from key migration destinations. The findings of this pilot study will provide preliminary data to support a proposal for a larger mixed-methods study in the research site, culminating in the design of an HIV prevention intervention with female migrants. Back to top

Numerous gender-transformative HIV/AIDS prevention interventions are carried out in developing country contexts with heterosexually-active women, but very little gender transformative HIV work is carried out with heterosexually-active men. This study qualitatively examines the impact of an HIV/AIDS and anti-violence program known as the One Man Can Initiative (implemented by Sonke Gender Justice, Cape Town, South Africa). Men will be recruited from Cape Town and Johannesburg, South Africa (N=120). The aims are to ascertain men’s changing conceptions of masculinity, their perceptions of shifts in gender roles, rights, and equity, and their perceptions of the ways in which shifts in gender roles and relations impact risk behaviors (alcohol, violence, sexual risk). This study will further an understanding of masculinity, gender relations, and health in South Africa and will help to improve the quality of HIV prevention programs and their efficacy with heterosexually-active men. Following this work, an NIMH R34 or R01 (to modify/adapt a program and rigorously test it) will be submitted for work with men in South Africa. Back to top

Preliminary data from pregnant women in rural Kenya indicate that fear of violence from a male partner is an important reason why some women refuse HIV testing, and that pregnant women who test HIV-positive or refuse testing may be more likely to be victims of violence. In response to these findings, we aim to develop an intervention on gender-based violence (GBV) for health workers who provide HIV-related services to pregnant women in this setting. First, in order to gain in-depth contextual understanding of gender-based violence, we will conduct focus groups and in-depth interviews with pregnant women, men, and a variety of service providers (health, law enforcement, education, women's groups, and village leadership) in rural Nyanza Province, Kenya. We will use the knowledge gained to develop a GBV intervention for health workers, taking advantage of existing Kenyan GBV training programs. Finally, we will conduct a preliminary pilot of the adapted intervention to assess feasibility and acceptability. The results of this pilot study will form the basis for future research on a larger scale to examine the impact of addressing GBV on prevention of HIV/AIDS. Back to top

Antiretroviral (ARV) therapy has greatly reduced HIV-related mortality, but treated patients still display excess mortality compared to HIV-negative individuals. This mortality is mostly driven by "non-AIDS defining conditions" such as cardiovascular and hepatic disease as well as non-AIDS related malignancies. One theory about the etiology of this excess mortality is that some patients with HIV may have systemic inflammation and/or states of hypercoagulability which persist during effective ARV therapy; these states may be central to the pathogenesis of the excess mortality seen in treated HIV patients. These theories have led many to revisit the question of the optimal timing of ARV initiation ("when to start"). While most now recommend ARV initiation when a patient's CD4+ count is < 350 cells/uL, there is mounting evidence suggesting possible long-term benefits of earlier initiation. This, however, has not been clearly demonstrated in randomized trials. Despite the links between levels of inflammatory biomarkers and mortality in some long-term treated patients, little is known about these biomarkers in the early stages of HIV infection. Similarly, little is known about these biomarkers and their evolution during ARV initiation. It therefore remains unknown how early different inflammatory states might be established, and whether early initiation of ARVs might prevent these from becoming chronic. We therefore aim to study the levels of well-validated biomarkers of inflammation and hypercoagulability in three patient groups: 1) patients initiating ARVs early, 2) patients deferring ARV therapy for the first several years of their disease, and 3) HIV-negative patients. The results of this study are expected to provide important information about HIV pathogenesis, inform ARV treatment decisions, and lay the groundwork for more intensive and prospective studies of these critical questions. Back to top

We recently reported the clinical and epidemiological characteristics of an atypical group of patients who developed Kaposi sarcoma (KS) in spite of having suppressed HIV and relatively higher CD4+ counts. Given similarities in clinical presentation between the KS of these long-term treated patients and the classical KS observed in HIV– elderly, we postulated that immunosenescence may be causally associated with emergence of KS. Preliminary results support this association, revealing higher levels of T cell immunosenescence marker CD57+ on both CD4+ and CD8+ T cells of HIV+ KS+ subjects vs. HIV+ KS– subjects (all on long term HAART). However, more information is needed concerning the role of premature immunologic aging in the more common manifestations of KS, particularly in KS that develops in poorly controlled or untreated HIV. In our proposed follow-up study, we investigate the role of T cell dysfunction and immunosenescence as a determinant of treatment responses in HAART-untreated patients who present with KS. Specifically we determine and compare markers of T cell immunosenescence in untreated patients whose KS persists or worsens during HAART (KS nonremitters) vs. wanes during HAART (KS remitters) Back to top