18th Report from: 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, Friday Feb 4th

HIV & Women:

In the first study described below study investigators treated ovariectomized macaques with estrogen to study the effect of estrogen on transmission and to understand vaginal transmission in post-menopausal animals. Researchers reported none of the estrogen treated monkeys were HIV-infected after being exposed intravaginally but the control monkeys became HIV-infected. 

The second study below discusses how chronic inflammation at the site of heterosexual transmission may be the cause of higher risk for infection. The rate of heterosexual transmission in Thailand is higher than in North America. Also, the rate of infection per exposure is higher in Thailand. In a study comparing Thai and US women, the study described below showed that that 84% of Thai and 14% of US women looked at in this study exhibited a chronic inflammatory T-cell infiltrate in the vaginal epithelium that, in Thai tissue, was associated with elevated levels (50 fold) of HIV RNA in the epidermis. Study authors say this chronic inflammation might lead to an accumulation of activated t-cells at the site of transmission which might act as targets for HIV-infection. 

Estrogen Protects against Vaginal Transmission of SIV.

S. SMITH^{1«2}, P. CHARKRABORTY^{1}, G. BASKIN^{3}, and P. MARX*^{3«4}. ^{1}Saint Michael's Med. Ctr. and ^{2}Univ. Med. and Dent. of New Jersey, Newark, NJ; ^{3}Tulane Regional Primate Res. Ctr., Tulane Univ. Med. Ctr., Covington, LA; and ^{4}Aaron Diamond AIDS Res. Ctr., Rockefeller Univ., New York, NY.

To assess the individual effects of estrogen and progesterone on SIV vaginal transmission and also to model HIV vaginal transmission in post-menopausal women, we studied ovariectomized macaques. 18 animals underwent bilateral ovariectomy. Subsequently, six animals received a progesterone implant; six animals received estrogen implants; and six animals received no implant. Hormone levels reached the expected values in each group. The untreated, ovariectomized animals did not have significant amounts either progesterone or estrogen; the estrogen treated animals had follicular phase levels of estrogen (avg. 399 pg/ml) and no detectable progesterone; the progesterone treated animals had luteal levels of progesterone (avg. 4.5 ng/ml) and no appreciable estrogen. Animals were then challenged intravaginally with SIVmac251 (640TCID_{50}) and studied serially to establish the presence or absence of infection. Virus was isolated from 5/6 progesterone treated animals and 6/6 untreated animals at both Days 14 and 42 post-challenge. Virus was not isolated from any of the estrogen treated animals at Days 14, 42, or 308. Accordingly, none of the estrogen treated animal seroconverted to SIV and none had detectable SIV proviral DNA in their PBMCs as determined by nested PCR. In summary, 5/6 progesterone treated and 6/6 untreated animals became infected after intravaginal challenge, while none of the estrogen treated animals became infected. The progesterone and untreated animals had thinned vaginal epithelia (avg. 4 microns), while the estrogen treated animals had much thicker vaginal epithelia (avg. 240 microns). Vaginal epithelial thickness, as seen in our prior study, inversely correlated with susceptibility to infection. These data suggest: 1. Women with thin vaginal epithelia, such as post-menopausal women, may be more susceptible to HIV-1 vaginal transmission; 2. Estrogen therapy may reduce this increased susceptibility.
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Chronic Inflammation with Increased HIV RNA Expression in the Vaginal Mucosa: Association with Heterosexual Transmission of HIV.

M. A. COHN*^{1}, S. S. FRANKEL^{2}, S. RUGPAO^{3}, M. A. YOUNG^{4}, G. WOLLETT^{4}, S. TOVANABUTRA^{3}, T. VANCOTT^{2}, L. BHOOPAT^{3}, S. BARRICK^{2}, T. C. QUINN^{5}, M. VAHEY^{2}, K. E. NELSON^{5}, and D. WEISSMAN^{6}. ^{1}Howard Hughes Med. Inst.-NIH Res. Scholars Program, Bethesda, MD; ^{2}Walter Reed Army Inst. of Res., Rockville, MD; ^{3}Chiang Mai Univ., Thailand; ^{4}Georgetown Univ., Washington, DC; ^{5}The Johns Hopkins Univ., Baltimore, MD; and ^{6}Univ. of Pennsylvania, Philadelphia.

Higher rates of heterosexual transmission of HIV have been observed in Thailand compared to North America. The risk of infection per exposure has also been reported to be higher in Thailand. Explanations for this observation include both host factors such as sexually transmitted diseases, and viral factors such as cellular tropism. To explore the role of host or viral factors at the site of exposure during heterosexual transmission, vaginal epithelial biopsies, blood, and cervical-vaginal lavage (CVL) from HIV seropositive Thai and American women were evaluated for blood and tissue viral load, histological makeup, and genital tract pathogens. Exclusion criteria included gross visual evidence of inflammation or infection on pelvic exam at the time of biopsy. Histological analysis revealed that 84% of Thai and 14% of US women exhibited a chronic inflammatory T-cell infiltrate in the vaginal epithelium that, in Thai tissue, was associated with elevated levels (50 fold) of HIV RNA in the epidermis. No associations between inflammation and patient reported sexually transmitted diseases or CVL analyses for gonorrhea, Chlamydia, Candida, Trichomonads, or bacterial vaginosis were observed. The higher rates and increased risk of heterosexual transmission in Thailand may be due, in part, to chronic inflammation at the site of heterosexual viral transmission leading to the accumulation of activated T cells. Such T cells might act as targets for initial viral infection and subsequently as reservoirs that support efficient transmission. Further studies on the inflammatory cells and viruses they harbor may lead to a better understanding of factors controlling HIV transmission. Additionally, studies aimed at finding the etiological agent(s) that cause the inflammation may lead to therapies that decrease the risk of transmission.