Human immunodeficiency virus-1 (HIV) epidemic continues to pose a major infectious disease threat to human health, affecting 38 million people worldwide. Additionally, about two million new HIV infections are diagnosed each year. The combination antiretroviral therapy (ART) is effective in suppressing HIV replication and reducing morbidity and mortality. However, ART is unable to eradicate the latent HIV reservoirs and does not consistently translate into complete immune recovery. Novel combination approaches are needed to prevent new infections along with therapies that are able to enhance and empower the host immune system for achieving full recovery in HIV infected individuals. HIV infection is characterized by CD4+ T cell loss, chronic immune activation and impaired host immune functions. A better understanding of the factors that induce immune modulation and enhance anti-viral immunity is important in developing innovative therapeutic or prevention strategies for HIV infection. In this dissertation project, we investigated cellular and viral factors that impact anti-HIV immunity by using the preclinical non-human primate model of AIDS. Two independent approaches were applied to investigate the impact of immune modulation on generating anti-viral immunity. In the first study (Chapter 2), the impact of mesenchymal stem cell (MSCs) therapy was investigated in enhancing anti-viral immunity and controlling chronic immune activation in chronically simian immunodeficiency virus-infected rhesus macaques. In the second study (Chapter 3), the effect of subclinical cytomegalovirus (CMV) infection on the induction of vaccine immunity in response to RhCMV/SIV and to inactivated influenza vaccine was investigated. Since immune cell subsets are an integral component of generating host immune response to vaccines and viral infections, we investigated the effect of SIV infection on the prevalence and functions of immune cells including T cell subsets and natural killer (NK) cells (Chapter 3). Chapter 2: Administration of allogenic mesenchymal stem cells to chronically SIV infected rhesus macaques resulted in enhanced levels of SIV specific antibody response and cytotoxic T cell activity. This increased anti-viral immunity was associated with partial restoration of activated B cell and T follicular helper cell subsets, enhanced mucosal lymphoid germinal center structure and increased localization and trapping of the virus in the lymphoid follicles. These changes coincide with a striking decline in viral RNA levels in peripheral blood and in gut mucosal lamina propria. The enhanced anti-viral immunity was associated with a gene signature enriched for the B and Tfh cell functions and enhanced antigen presentation. Chapter 3: There is a substantial level of variation at the population level in the immune response to anti-viral vaccines and their efficacy which is attributed to host immune status. Several factors including the presence of subclinical viral infections, age and microbiota can modulate the immune functionality. To investigate the factors that contribute to individual variation in immune response to anti-viral immunity, we assessed host immune response in rhesus macaques following immunization with two vaccines, an inactive trivalent influenza vaccine (TIV) and an SIV vaccine presented in an attenuated live CMV vector (RhCMV/SIV). Animals that generated higher vaccine immunity (anti-viral antibodies) to influenza vaccine were identified as high responders. The same animals also mounted a higher immune response to SIV vaccine. There were no marked differences in the composition of the microbiota at the genus level. However, Paraprevotelaceae was enriched in the high vaccine responder group and its prevalence positively correlated with the magnitude of antibody responses to influenza and SIV gag vaccines. The most pronounce effect on vaccine immunity correlated with the presence of subclinical CMV infection. The CMV-negative animals had higher vaccine responses compared to CMV positive animals. Thus, the presence of subclinical CMV infection and immune activation modulated immunity to anti-viral vaccines. Chapter 4: Composition and function of immune cell subsets determine host immune response to vaccines or viral infections. Therefore, we sought to investigate the effects of SIV infection on T cell subsets and NK cells in peripheral and mucosal compartments of SIV-infected rhesus macaques and analyze in the context of virological and immunological outcomes. As previously demonstrated, a pronounced depletion of CD4+ T cells was detected both in peripheral blood and intestinal tissues. A rapid increase in the total frequency of NK cells was observed following the acute phase of SIV infection, suggesting that these NK cells might have contributed to the control of virus replication during this stage. There were no significant differences observed in total NK cells in the gut but the percentage of proliferating NK cells had a significant increase at this stage. Summary: Research studies presented in this dissertation have identified the impact of immune modulation through subclinical viral infections or through mesenchymal stem cell therapy, on the host immune responses to viral infection and vaccines in the SIV-infected rhesus macaque model of AIDS. The study identified a novel functionality of MSC in enhancing anti-viral immunity and highlights an opportunity to boost anti-viral immunity in HIV infection. Our findings on the impact of CMV on dampening anti-viral vaccine immunity has identified one of the mechanisms of immune heterogeneity in vaccine responses at the population level. Collectively, these studies have identified mechanisms that can enhance therapeutic and prevention approaches for HIV infection.