HIV sexual transmission  
The most frequent route of HIV acquisition is heterosexual transmission, however the previous animal models fail to reproduce critical aspects of the process, aspects that can determine the value of specific intervention or prevention strategies.  Using the chimeric HIV, EcoHIV, that infects mice we developed a system of virus sexual transmission during mouse mating.  This approach preserves all of the features present in the male inoculum including free HIV, infected cells, and the proposed transmission enhancer in semen, SEVI.  Likewise, the female reproductive tract remains native, without the trauma associated with other animal models of sexual transmission, and exhibits the post-coital inflammatory cascade that brings HIV target cells to the reproductive tract, which may influence the success of transmission.  Among the most interesting findings we obtained is the resistance of female mice to HIV sexual transmission during estrus, when estrogen peaks locally.  It is noteworthy that females in estrus remain susceptible to HIV infection by injection indicating the utility of closely modeling genuine sexual transmission.    We also found that induction of both adaptive and innate immune responses prevented HIV sexual transmission, observations we intend to pursue to develop simple and cheap routes, controlled by women, to prevent HIV acquisition.

Immune responses to prevent HIV transmission
HIV naturally induces both adaptive and innate protective immune responses, an observation overshadowed by its induction of immunodeficiency in most infected human beings.  However, mice respond to HIV infection robustly, generating cytotoxic T cells that can stop infection; this protection can be enhanced by immunization with HIV DNA vaccines designed for clinical use.  Similarly, mice infected by HIV mount significant innate immune responses.  A major facet of innate immunity, the Type I interferon response, is essential for the control of infection by many viruses, including HIV.  Interferon related genes encode some of the most potent restriction factors for HIV replication, including APOBEC 3G and tetherin.  We demonstrated that HIV infection naturally induces protective interferon responses by showing that mice lacking the interferon receptor are both more susceptible and suffer more pathogenic infection than do wildtype mice.  We are now applying classical techniques of vaccination for adaptive immunity to elicit optimal innate immune responses, particularly in the female reproductive tract, to prevent HIV sexual transmission.  Distinct routes of vaccination also prime systemic protective responses.  Our system can take advantage of the extensive repertoire of genetically engineered and knockout mice in single elements of immune pathways to define the basis of protective responses, an avenue that is not available in other HIV infection approaches.