The influence of biological sex on disease progression in HIV-1-infected individuals has been focused on the chronic stage of infection, but little is known about how sex differences influence acute HIV-1 infection. We observed profound differences in viral load and CD4⁺ T cell activation from the earliest time points in men and women in a Zambian heterosexual acute infection cohort. Women exhibited a >2-fold higher rate of CD4⁺ T cell loss despite significantly lower viral loads (VL) than men. The importance of studying acute infection was highlighted by the observation that very early in infection, women exhibited significantly higher levels of CD4⁺ T cell activation, a difference that was lost over the first 3 years of infection as activation in men increased. In women, activation of CD4⁺ T cells in the acute phase was significantly correlated with plasma levels of 17β-estradiol (E2). However, unlike in men, higher CD4⁺ T cell activation in women was not associated with higher VL. In contrast, a higher E2 level in early infection was associated with lower early and set-point VL in women. We attribute this to an inhibitory effect of estradiol on virus replication, which we were able to observe with relevant transmitted/founder viruses in vitro Thus, estradiol plays a key role in defining major differences between men and women during early HIV-1 infection by contributing to both viral control and CD4⁺ T cell loss, an effect that extends into the chronic phase of the disease.IMPORTANCE Previous studies have identified sex-specific differences during chronic HIV-1 infection, but little is known about sex differences in the acute phase, or how disparities in the initial response to the virus may affect disease. We demonstrate that restriction of viral load in women begins during acute infection and is maintained into chronic infection. Despite this, women exhibit more rapid CD4⁺ T cell loss than men. These profound differences are influenced by 17β-estradiol, which contributes both to T cell activation and to reduced viral replication. Thus, we conclude that estradiol plays a key role in shaping responses to early HIV-1 infection that influence the chronic phase of disease.

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