Inclusion Criteria:

Potential index (HIV-infected) participants must meet the following criteria (by self-report, unless otherwise indicated) in order to be eligible for inclusion in the study:

• Of legal age to provide independent informed consent for research per local regulations and guidelines.
• Able and willing to provide written informed consent to be screened for and to take part in the study. (Note: Index participants who are not willing to provide genital tract specimens for HIV viral load quantitation, but are willing to undergo all other study procedures, will be considered eligible for inclusion in the study.)
• Part of a heterosexual couple in which one partner meets the study eligibility criteria for index participants and the other partner meets the study eligibility criteria for partner participants. Couples are defined as partners who are sexually active and plan to remain in the relationship for at least one year. Each site will develop appropriate criteria for determining whether a couple is likely to remain in the relationship (i.e., married, duration of partnership, cohabitation, have children).
• Has had vaginal intercourse with the partner participant at least three times in the last three months.
• Plans to maintain his/her relationship with the partner participant for the next 24 months.
• HIV-infected based on positive EIA.
• HSV-2-seropositive based on the Focus HSV-2 EIA (performed by study staff) with an index ratio of at least 3.5 or if Focus EIA IN 1.1-3.4, confirmed by HSV-2 WB dot-blot performed at the UW.
• CD4 cell count (performed by study staff) of at least 250 cells/mm3.
• No history of any clinical AIDS-defining diagnoses.
• Able and willing to provide adequate locator information for study retention purposes, as defined by local standard operating procedures.

Potential partner (HIV-uninfected at enrollment) participants must meet the following criteria (by self-report, unless otherwise indicated) in order to be eligible for inclusion in the study:

• Of legal age to provide independent informed consent for research per local regulations and guidelines.
• Able and willing to provide written informed consent to be screened for and to take part in the study.
• Part of a heterosexual couple in which one partner meets the study eligibility criteria for index participants and the other partner meets the study eligibility criteria for partner participants.
• Has had vaginal intercourse with the study partner at least three times in the last three months.
• Plans to maintain his/her relationship with the index participant for the next 24 months.
• HIV-uninfected based on negative HIV EIA tests.
• Able and willing to provide adequate locator information for study retention purposes, as defined by local standard operating procedures.

Exclusion Criteria:

Potential index (HIV-infected) participants who meet any of the following criteria (by self-report, unless otherwise indicated) will be excluded from the study:

• Current use of combination antiretroviral therapy
• Known history of adverse reaction to acyclovir.
• Known history of persistent genital ulcers unresponsive to episodic acyclovir therapy.
• Known plans to re-locate or travel away from the study site for more than two consecutive months during the next 24 months.
• Pregnant, based on participant self-report or urine testing performed by study staff. (Note: Self-reported pregnancy is adequate for exclusion from the study. A documented negative test performed by study staff is required for inclusion.)

Potential partner participants who meet any of the following criteria (by self-report, unless otherwise indicated) will be excluded from the study:

• Has had sexual intercourse with a partner other than the index participant in the last two months.
• Known plans to re-locate or travel away from the study site for more than two consecutive months during the next 24 months.