Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy

Abstract

Background: Acute HIV infection (AHI) is a critical phase of infection when irreparable damage to the immune system occurs and subjects are very infectious. We studied subjects with AHI prospectively to develop better treatment and public health interventions.

Methods: Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA). Twenty-two cytokines/chemokines were measured from enrollment through week 24.

Results: Thirty-seven AHI subjects were studied. In 7 participants with limited exposure windows, the median exposure to HIV occurred 14 days before symptom onset. Lack of viral sequence diversification confirmed the short duration of infection. Transmission dates estimated by SGA/sequencing using molecular clock models correlated with transmission dates estimated by symptom onset in individuals infected with single HIV variants (mean of 28 versus 33 days). Only 10 of 22 cytokines/chemokines were significantly elevated among AHI participants at enrollment compared to uninfected controls, and only 4 participants remained seronegative at enrollment.

Discussion: The results emphasize the difficulty in recruiting subjects early in AHI. Viral sequence diversity proved accurate in estimating time of infection. Regardless of aggressive screening, peak viremia and inflammation occurred before enrollment and potential intervention. Given the personal and public health importance, improved AHI detection is urgently needed.

Conflict of interest statement

Competing Interests: C.G. has received research support from Bristol Myers Squibb and Gilead Sciences for studies which participants in this study could co-enroll on, but not for the CHAVI 001 study. C.H. has received grant support and/or consulting/honoraria from BMS, GSK, Merck, Tibotec, Gilead, Myriad Pharmaceuticals, Pfizer, none of which is related to this study. D.M. has received research support from Bristol Myers Squibb, Gilead Sciences, Merck, Abbott, and Roche, but none for this study, and is a honoraria for professional services to Bristol Myers Squibb, Merck, Chimerix, and Tibotec Therapeutics. J.E. receives research support from Merck and GlaxoSmithKline which is not related to this study and is a consultant to Bristol Myers Squibb, Merck, and Tibotec Therapeutics. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. The remaining authors have no competing interests to declare.

Figures

Figure 1. Timeline of AHI: estimated HIV exposure, symptom onset, presentation to care, AHI diagnosis and enrollment in subjects with a narrow window of exposure based on self-report.

A narrow window of exposure is defined as all patients with high or medium exposure date confidence (n = 6), plus patients with a one-time exposure in the 8 weeks prior to diagnosis with a partner of unknown status (n = 4).

Figure 2. Estimated dates of infection based on symptom onset (x axis) vs. BEAST (y axis) in 15 patients with single variant transmissions.

Infection dates were inferred by subtracting 14 days from symptom onset and compared to BEAST calculations relative to sampling of blood plasma for SGA env sequence generation. The slope of the line is 1.166±0.2995 with R2 = 0.54 for all 15 patients.

Figure 3. Viral loads and plasma levels of IFNα, IL-15, IL-18 and IL-1βin sample time courses from three subjects acutely infected with HIV.

A is a US plasma donor, whose sample time course is plotted in days and is aligned relative to the time (designated day 0) when the plasma viral load first reached 100 copies/ml (i.e. the start of the viral expansion phase). B and C are CHAVI 001 subjects, whose sample time courses are plotted in weeks, and are aligned relative to the time of study enrollment (week 0). Subject B started ART just after study enrollment, as indicated by the black arrow. Viral load data is plotted as open squares joined by dotted lines, and is expressed as log10 RNA copies/ml. Data for each cytokine is plotted as filled symbols joined by solid lines, and is expressed as pg/ml.

Figure 4. Comparative analysis of plasma levels of 10 selected analytes at enrollment and week 16–24 in AHI subjects commencing ART, AHI subjects choosing not to start ART and HIV-seronegative controls.

Plasma levels of 22 cytokines and chemokines were measured in sample time courses from a total of 23 AHI subjects and 21 HIV seronegative controls (Neg). Data for ten analytes (IL-1β, IL-2, IL-7, IFNγ, GM-CSF, MIG, MIP-1β, IP-10, IL-18 and IL-15, each expressed as pg/ml plasma) is shown at A) the enrollment time point (prior to commencement of therapy), when samples were available from 10 CHAVI 001 AHI subjects who chose to commence ART after the enrollment time point (AHI - T) and 12 AHI subjects who chose to remain untreated (AHI - UT) and B) week 16 or 24, when samples were available from 11 CHAVI 001 AHI subjects who chose to commence ART after the enrollment time point (AHI - T) and 7 AHI subjects who chose to remain untreated (AHI - UT). In both A and B, data are also shown from 21 HIV-seronegative subjects (sampled at the enrollment time point), except for IL-18 where n = 14 and IL-15 where n = 10. Each symbol represents data for an individual subject, and horizontal lines represent the median analyte level in the subject groups. Bars at the top of each graph show statistically significant differences between groups (p