Research in our laboratory focuses on the following areas: 1) The multifaceted role of neutrophils in HIV-1-infection. In recent years, a new appreciation of the role of neutrophils in regulating the immune system has emerged. Neutrophils are the most abundant leukocyte population and are traditionally recognized as essential effector cells of the innate immune system in the host defense against invading organisms. While neutrophils have been shown to play important roles in viral pathogenesis, a knowledge gap exists in our understanding of the function of neutrophils in individuals infected with human immunodeficiency virus-1 (HIV-1). The data recently accumulated in our laboratory reveals the multifaceted role of neutrophils in HIV-1-infection where they exert both pro-inflammatory and anti-inflammatory effects. We demonstrated that chronic HIV-1-infection and ongoing microbial translocation is associated with the induction of neutrophils with immunosuppressive activity that significantly contribute to the suppression of T cell function in HIV-1-infection. In addition, we show that enhanced neutrophil extracellular trap (NET) formation in HIV-1-infected subjects may contribute to the incidence of inflammatory-driven disease through direct effects of NETs or indirectly through NET mediated effects on macrophage function. These findings show that the role of neutrophils in HIV-1-infection is more complex than previously recognized. 2) Mucosal antibody production and the pathogenesis of HIV-1 infection. The decline of CD4+ T cells, a hallmark of HIV-1 infection and indicator of disease progression, is caused primarily by chronic activation of immune system; however, the underlying causes of this activation remain unclear. We hypothesize that HIV-1 infection is associated with a severe reduction of IgA responses to common microbial and food antigens proportionally to the extent of CD4+ T cell depletion and polyclonal activation of IgA-producing B cells at mucosal tissues. We investigate whether the inability to mount specific IgA responses results in increased absorption of environmental antigens to the systemic compartment contributing to the chronic activation of CD4+ and CD8+ T cells characteristic for HIV-1 infection. 3) Effect of sex steroid hormones and hormonal contraception on the immunobiology of HIV-1 infection. Worldwide, increasing number of women uses oral or injectable hormonal contraceptives. However, inadequate information is available to aid women and healthcare professionals in weighing the potential risks of hormonal contraceptive use in individuals living with human immunodeficiency virus-1 (HIV-1) or at high risk of infection. Numerous epidemiological studies suggest that progesterone-based contraceptives increase the risk of HIV-1 infection in humans, accelerate disease progression, and increase viral shedding in the genital tract. In contrast to progesterone, systemic or intravaginal treatment with estrogen efficiently protects female rhesus macaques against the transmission of SIV, likely by enhancing the natural protective properties of the lower genital tract mucosal tissue. We investigate the effect of progesterone, medroxyprogesterone, and estrogen on various immune functions in HIV-1-infected women and uninfected controls. 4) HIV-1 vaccine development. SIV infection in macaques closely resembles human AIDS and represents the best model for assessing the protective efficacy of candidate HIV-1 vaccine. Previously, we demonstrated that immunization with an attenuated recombinant poxvirus vector NYVAC-SIV in combination with a DNA-SIV vaccine candidate expressing the structural genes of SIV resulted in high levels of virus-specific CD4+ and CD8+ T-cell responses and in a significant suppression of viremia following an exposure to the highly pathogenic SIV virus. In addition, we showed a significant improvement following an addition of early/auxiliary genes rev, tat, and nef to the vaccine. Currently, we are developing and testing new vaccine strategies. 5) Design of novel strategies for the immunotherapy of cancer. Immunization of patients with tumor-associated antigens results in the induction of tumor-specific immune responses that can significantly restrict or eliminate the spreading tumor. We are testing the possibility of transplantation with genetically modified hematopoietic stem cells (HSCs) targeting the expression of antigen to activated dendritic cells as a strategy for long-term cancer immunotherapy. In a second project, we investigate immunization with antigen-presenting genetically modified B cells specifically targeted to secondary lymphoid tissue.
