Amplified transmission of HIV-1: comparison of HIV-1 concentrations in semen and blood during acute and chronic infection

Abstract

Objectives: This study was conducted to compare viral dynamics in blood and semen between subjects with antibody negative, acute HIV-1 infection and other subjects with later stages of infection.

Design: A prospective cohort study was embedded within a cross-sectional study of HIV screening in a Lilongwe, Malawi STD clinic.

Methods: Blood samples from HIV antibody negative or indeterminate volunteers were used to detect HIV RNA in plasma using a pooling strategy. Blood and seminal plasma HIV-1 RNA concentrations were measured over 16 weeks.

Results: Sixteen men with acute HIV infection and 25 men with chronic HIV infection were studied. Blood viral load in subjects with acute HIV infection was highest about 17 days after infection (mean +/- SE, 6.9 +/- 0.5 log10 copies/ml), while semen viral load peaked about 30 days after infection (4.5 +/- 0.4 log10 copies/ml). Semen viral load declined by 1.7 log10 to a nadir by week 10 of HIV infection. Semen and blood viral loads were more stable in chronically infected subjects over 16 weeks. Higher semen levels of HIV RNA were noted in subjects with low CD4 cell counts.

Conclusions: These results provide a biological explanation for reported increases in HIV transmission during the very early (acute) and late stages of infection. Recognizing temporal differences in HIV shedding in the genital tract is important in the development of effective HIV prevention strategies.

Fig. 1. Flowchart of the study population

Cohorts contributing data to this report are represented by the shaded boxes. RT, Rapid testing; WB, insert full term here.

Fig. 2. HIV-1 viremia and HIV-1 shedding over time in acutely (a) or chronically (a) HIV infected men

HIV-1 RNA measurements in blood plasma (grey) and seminal plasma (black) are shown for 16 weeks. The acute infection data (a) are shown with the x-axis representing the time from estimated infection date, which is different for each subject. Chronic infection data (b) are shown with the x-axis representing the time from study entry and therefore appear to be more synchronized. Sixteen acutely infected subjects contributed 60 blood and 34 semen time-points; 25 chronically infected subjects contributed 123 blood and 89 semen time-points. HIV-1 shedding was detectable in 26/34 (76%) acute semen samples and in 70 (79%) of 89 chronically infected semen samples.

Fig. 3. Viral dynamics in acute HIV infection

To describe the magnitude and timing of trends in the observed data, expected concentration versus time curves for mean HIV-1 RNA level were generated using a statistical model. Shown here are mean estimates for blood (grey) and semen (black) data along with their 95% confidence intervals (dotted lines) for acute infection subjects only. The final, unified model used in all primary analyses was a linear mixed-effects model including all data, featuring two-knot polynomial regression splines for acute subject blood and semen HIV-1 RNA level that were quadratic for day 0 to day k1, cubic for days k1 to k2, and constant for days k2 to day 200 [17]. For [k1,k2] was taken to be [18, 60.66] for blood and [30, 68.39] for semen. From an assumed mean HIV-1 RNA level of − 4 logs on day 0 [14,15], the model featured a peak in viral load during the first 3–4 weeks followed by decay of the viral loads to nadirs and chronic levels by 8–10 weeks after initial infection. To account for a possible relationship between shedding and CD4 cell count, chronic infection blood and semen data were stratified by the median CD4 cell count for chronically infected cohort subjects (351 cells/μl). Reported model estimates were robust to substantial changes in model assumptions (including assumed day 0 viral load and to the placement of regression knots).

Fig. 4. HIV viremia and shedding, measured over the natural course of HIV infection

Box-and-whisker plots represent HIV-1 RNA levels in blood (grey) and semen (black), estimated for individual study subjects by disease stage. Numerical values at each time-point were estimated for each individual subject by empirical best linear unbiased prediction (eBLUP) making use of the final, unified best fit model including all observed data. Boxes and whiskers denote the 25^th, 75^thquartiles and total range of values. Internal circles and horizontal lines represent mean and median, respectively. Data for acutely infected subjects are shown at weeks 4, 8 and 16. The data for chronically HIV infected subjects represent the mean values of specimens collected over 16 weeks and are shown separately for high (>350 cells/μl) and low (≤ 350 cells/μl) CD4 cell count subjects.