The acute HIV infection: implications for intervention, prevention and development of an effective AIDS vaccine

Abstract

Effective preventive measures against HIV must function near the time of virus transmission to prevent the establishment of a chronic infection. Low-dose SIV/SHIV infections by multiple routes lead to remarkably rapid systemic dissemination of virus and large numbers of infected cells during the initial weeks of the acute infection. Here we describe the narrow time-frame during which potent post-exposure interventions such as anti-retroviral therapy or the administration of high-titered neutralizing antibodies can block the establishment of the in vivo infection. This short window of opportunity is applicable to HIV infections and represents a formidable challenge for developing effective chemoprophylaxis and vaccine approaches.

Figure 1

Representative SIV infectivity profiles in rhesus macaques following low dose inoculations by different routes. The curves shown are based on reports for inoculation of SIV by the IV (100 TCID₅₀) [14], IR (930 TCID₅₀) [16], and IVag (1000 TCID₅₀) [20] routes. The hypothetical HIV curve is based on an eclipse period of 10 days and peak levels of plasma viremia occuring on day 25 post exposure [3,17]. The inset depicts the levels of plasma viremia measured in macaques inoculated with 100 or 10,000 TCID₅₀ of SIVmac239 by the IV route [14,15].

Figure 2

Massive numbers of CD4⁺ T lymphocytes become infected systemically by SIV and SHIV during the acute infection. (a) Cell-associated viral DNA present in memory CD4⁺ T cells, recovered and sorted from the indicated tissues of SIVmac 251 infected animals (adapted from reference [23]. (b) Percentage of naïve and memory CD4⁺ T cells releasing infectious particles (limiting-dilution/co-cultivation with uninfected PBMC) on days 6 and 10 following IV SHIV_DH12R inoculation (adapted from reference [30]). (c) Frequency of naïve and memory CD4⁺ T cells containing integrated viral DNA in 4 monkeys at day 10 post SHIV_DH12R infection (adapted from reference [32]).

Figure 3

Virus producing lymph node cells from macaques are not activated during the acute infection. Mesenteric lymph node sections from two SHIV_DH12R infected monkeys (day 10 PI) were analyzed by combined immunostaining for Ki-67 (red) and in situ hybridization (green) (adapted from reference [30]). Superimposed images are shown in the right panels.

Figure 4

Post-exposure administration of an anti-retroviral drug or NAbs. (a) A 4-week course of the reverse transcriptase inhibitor, tenofovir, was initiated in 6 animals, 48h following IV inoculation of 100 TCID₅₀ of SIVmac239 (colored curves). Two untreated monkeys (black curves) served as controls (adapted from reference [41]). (b) Polyclonal anti-viral NAbs were transferred at 6h (four macaques) or 24h (2 macaques) post IV inoculation of SHIV_DH12 (75 TCID₅₀). The dashed curves represent two recipients of non-neutralizing antibodies (adapted from reference [41]).