Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP). Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs.

For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field.

MaterialThe HIV-1 Nef protein is a major determinant of HIV-1 pathogenicity. It has been found to induce thymocyte depletion, but the mechanisms involved are not completely understood. Also, nothing is known about its effects on thymocyte selection. We used the CD4C/HIV Nef transgenic (Tg) mice, which develop a profound CD4 + T cell lymphopenia, to study their thymic development. We report that HIV-1 Nef causes depletion of double-positive thymocytes and impairs selection and lineage commitment of CD4 + single-positive thymocytes. This latter defect could be relieved by increasing the affinity of the TCR-MHC interaction or by allowing CD4 + T cell maturation to proceed in absence of the CD4 tail, in double-Tg (Nef 3 CD4 tailless ) mice or in the presence of constitutively active Tg Lck Y505F . These rescue strategies also resulted in reversal of peripheral CD4 + T cell lymphopenia. Our data indicate that impairment of Lck-mediated CD4 coreceptor signaling by Nef is an important in vivo mechanism of HIV-1 pathogenesis.

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The primordial germ cells of the human female embryo are recognizable at approximately 24 days.' Although about 100 germ cells are present at the beginning of their migration from the posterior wall of the yolk sac to the presumptive gonad, mitosis provides for their increase to 7 million within the ovary by the fifth month of ovarian development.'The gonads first arise as the gonadal ridges. Recent studies3 indicate that the coelomic epithelium becomes stratified, forming a slight protrusion of the developing gonad into the coelomic cavity. The coelomic epithelial cells develop into short "pillars," which form what is known as the "primary" sex cords. Following this, cells from the mesonephros are incorporated into the gonad forming "primordial" sex cords which become displaced toward the peripheral region of the gonad both by enlargement of the cords and by formation of the medulla at the base of the ovary. The primordial sex cords break into irregular clusters that contain groups of primitive germ cells. They then differentiate into "folliculogenous" sex cords, which give rise to follicular cells. The cords break into irregular clusters that contain groups of primitive germ cells. These clusters are later replaced by a vascular stroma, forming the ovarian medulla. Moreover, recent s t~d i e s~.~ show that laminin forms a matrix of the basal compartment of the surface epithelium continuous with that surroundmg the nests of oogonia in the developing ovaries of both pig and rabbit. Taken together, the preponderance of evidence suggests that some progenitor epithelial cells of the developing ovary may be descendants of the surface epithelium.