Recent studies have suggested that HIV-1 infectivity may be highest early after HIV-1 acquisition. In one prospective study, the risk of transmission to a sexual partner during the first 2.5 months after HIV-1 seroconversion was nearly 12-fold higher than during chronic infection . It has therefore been suggested that early HIV-1 infection may play a dominant role in epidemic HIV-1 spread . Early HIV-1 infection is characterized by high levels of systemic viral replication, but there is little information on the levels of genital HIV-1 at that time, which may be more relevant to infectivity. Here, we aimed to investigate HIV-1-RNA levels in the female genital tract during early HIV-1 infection.
Between 1993 and 2003, we enrolled HIV-1-seronegative female sex workers in Mombasa, Kenya, in a prospective cohort study of HIV-1 acquisition . At approximately monthly visits, HIV-1 and sexually transmitted infection (STI) screening was performed. If HIV-1 seroconversion had occurred, plasma and a cervical specimen were collected by gently inserting a swab 1 cm into the cervical os and rotating two full turns. Plasma and cervical swabs were collected approximately quarterly thereafter. HIV-1 RNA was measured using the Gen-Probe HIV-1 viral load assay and lower limits of quantification of 100 copies/ml plasma and 50 copies per swab were applied [3,4]. Informed consent was obtained from all participants. The study was approved by the ethical review committees of the University of Nairobi, the University of Washington, and the Fred Hutchinson Cancer Research Center.
A combination of HIV-1 serological and plasma RNA data were used to estimate dates of HIV-1 acquisition, as previously described . For this analysis, we selected all women who had a set of plasma and cervical samples from within 90 days of infection and another plasma/cervical set from 4–24 months after infection, after the establishment of steady-state systemic viral replication (known as viral setpoint). Each woman thus served as her own control. If more than one setpoint measurement was available, the first was used.
A total of 60 women met these criteria: 11 whose early visits were within 30 days of HIV-1 acquisition, 23 whose early visits were 31–60 days after HIV-1 acquisition, and 26 whose early visits were 61–90 days after HIV-1 acquisition. Setpoint samples were collected at a median of 194 days (interquartile range 156–260) after HIV-1 acquisition. There were no statistically significant differences in the timing of setpoint samples among the three study groups. The median age was 30 years (interquartile range 26–35).
Cervical HIV-1-RNA levels were significantly higher in early samples compared with setpoint samples (mean 3.43 versus 2.85 log10 copies/swab, respectively, P < 0.001, paired samples t-test). Generalized estimating equations were used to compare early with setpoint cervical HIV-1-RNA levels (see Table 1). In unadjusted analysis, the difference between early and setpoint cervical HIV-1 RNA decreased in a step-wise fashion with increasing time from HIV-1 acquisition: by 0.89 log10 copies per swab for within 30 days (P < 0.001), by 0.53 log10 copies per swab for 31–60 days (P = 0.02), and by 0.49 log10 copies per swab for 61–90 days (P = 0.02). The magnitude of these coefficients decreased when adjusted for the HIV-1 plasma viral load, suggesting that much of the difference was associated with higher systemic viral replication during early infection. However, a difference of 0.68 log10 copies per swab between early and setpoint viral levels remained after adjustment for plasma viral load for women whose early samples were collected within 30 days of infection.
An additional multivariate model was constructed, further adjusting for the presence of a cervical STI, which has been associated with increased genital HIV-1 replication . In this model, samples from within 30 days of HIV-1 acquisition retained increased cervical RNA levels (by 0.45 log10 copies per swab, P = 0.006). The HIV-1 plasma viral load and cervical STI were also independently associated with significantly higher cervical HIV-1-RNA levels.
There has been considerable recent interest in the contribution of early HIV-1 infection to sexual HIV-1 transmission dynamics , but very few studies on the presence of virus in the female genital tract during early HIV-1 infection have been conducted. To our knowledge, the largest study included only two women . Therefore, the data presented here are the first to characterize a key marker of early HIV-1 infectivity in women.
The genital tract viral load was highest in the first month post-infection, and then gradually decreased, a pattern similar to that observed for plasma viral replication. Studies of individuals with chronic HIV-1 infection have generally found that plasma viral load is the strongest predictor of genital HIV-1 concentrations. In this study, however, cervical viral levels during the first month after infection were higher than predicted by the plasma virus load, suggesting that the female genital tract may to some degree be a compartment for independent early virus replication.
In conclusion, the first months after HIV-1 acquisition are probably a time of high infectivity, perhaps especially during the first 30 days, when genital HIV-1-RNA levels may be enhanced beyond what is expected based on systemic viral replication. As has been observed during chronic HIV-1 infection, genital HIV-1 levels during early HIV-1 infection are also increased by the presence of STI. Efforts to identify, counsel, and potentially treat individuals with acute HIV-1 infection, including treatment for concurrent STI, might have significant public health effects on HIV-1 transmission.
Sponsorship: This project was supported by the National Institutes of Health through grants AI-38518 and AI-33873.
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