Genital herpes (HSV-2) is the most common cause of genital sores worldwide, and the presence of genital sores is a significant risk factor for becoming infected with HIV. This study will test the effectiveness of twice-daily dosing of acyclovir, a commonly prescribed anti-herpes drug, in preventing HIV infection in HSV-2 infected women who sleep with men (WSM) and men who sleep with men (MSM).

Study hypothesis: Given that genital herpes is a significant risk factor to HIV acquisition, twice-daily HSV-2 suppressive therapy - 400 mg of acyclovir - will prevent HIV infection among high risk, HSV-2 seropositive WSM and MSM.

Many studies have shown that prior HSV-2 infection is associated with an increased risk for HIV infection. Acyclovir is the most widely studied and clinically utilized antiviral for the suppression of HSV-2 infection. This study will evaluate the efficacy of twice-daily dosing of acyclovir in preventing HIV infection in both WSM and MSM with genital herpes. For this study, WSM will be enrolled in Lusaka, Zambia; Harare, Zimbabwe; and Johannesburg, South Africa; MSM will be enrolled in Lima and Pucallpa, Peru; Seattle, Washington, USA; New York City, New York, USA; and San Francisco, California, USA.

Participants will be enrolled for 12 months in this study and will be randomly assigned to one of two study arms. The first arm will receive 400 mg acyclovir twice daily; the second arm will receive placebo. Follow-up visits will occur monthly. Participants will be tested for STDs, including HIV and syphilis, at each visit and treated as necessary; participants will also be given adherence and condom counseling, risk behavior and sexual history questionnaires, and genital symptoms questionnaires at all study visits. Medical history will be assessed and participants will undergo blood work at Months 3, 6, 9, and 12.

Inclusion Criteria For All Participants:

• HIV-uninfected
• HSV-2 infected
• Plans to stay in the area for the duration of study participation
• Willing and able to provide consent, undergo clinical evaluations, take study drugs, adhere to follow-up schedule, and provide adequate locator information

Inclusion Criteria for MSM:

• At least 1 episode of anal intercourse with another man within 6 months of study entry

Inclusion Criteria for WSM:

• At least 1 episode of unprotected vaginal sex within 6 months of study entry

Exclusion Criteria For All Participants:

• Current enrollment in another HIV vaccine or prevention trial
• History of adverse reaction to acyclovir
• Current or planned use of famiciclovir, valacyclovir, or acyclovir for genital HSV. Use of short-course antiviral therapy for herpes zoster after enrollment is allowed.
• Known plans for travel away from study site for more than 2 months

Exclusion Criteria for MSM:

• In a mutually monogamous relationship with an HIV uninfected partner throughout the past 2 years
• Reported sex at birth as female

Exclusion Criteria for WSM:

• Pregnancy at screening or enrollment