Primary human immunodeficiency virus type 1 (HIV-1) infection during HIV-1 Gag vaccination

Abstract

Vaccination for human immunodeficiency virus type 1 (HIV-1) remains an elusive goal. Whether an unsuccessful vaccine might not only fail to provoke detectable immune responses but also could actually interfere with subsequent natural immunity upon HIV-1 infection is unknown. We performed detailed assessment of an HIV-1 gag DNA vaccine recipient (subject 00015) who was previously uninfected but sustained HIV-1 infection before completing a vaccination trial and another contemporaneously acutely infected individual (subject 00016) with the same strain of HIV-1. Subject 00015 received the vaccine at weeks 0, 4, and 8 and was found to have been acutely HIV-1 infected around the time of the third vaccination. Subject 00016 was a previously HIV-1-seronegative sexual contact who had symptoms of acute HIV-1 infection approximately 2 weeks earlier than subject 00015 and demonstrated subsequent seroconversion. Both individuals reached an unusually low level of chronic viremia (<1,000 copies/ml) without treatment. Subject 00015 had no detectable HIV-1-specific cytotoxic T-lymphocyte (CTL) responses until a borderline response was noted at the time of the third vaccination. The magnitude and breadth of Gag-specific CTL responses in subject 00015 were similar to those of subject 00016 during early chronic infection. Viral sequences from gag, pol, and nef confirmed the common source of HIV-1 between these individuals. The diversity and divergence of sequences in subjects 00015 and 00016 were similar, indicating similar immune pressure on these proteins (including Gag). As a whole, the data suggested that while the gag DNA vaccine did not prime detectable early CTL responses in subject 00015, vaccination did not appreciably impair his ability to contain viremia at levels similar to those in subject 00016.

FIG. 1.

HIV-1 infection courses of subjects 00015 and 00016. The levels of plasma viremia and blood CD4⁺ T-lymphocyte levels are plotted for subject 00015 (top graph) and subject 00016 (bottom graph). For subject 00015, the vaccinations with Gag DNA are indicated by arrowheads, and the total Gag-specific IFN-γ ELISPOT response during the vaccine trial is plotted. The shaded regions indicate the intervals between the last negative and first positive HIV-1 ELISAs. The dotted lines indicate the time of onset of symptoms consistent with primary HIV-1 infection.

FIG. 2.

Magnitude and breath of the HIV-1-specific CTL responses in subjects 00015 and 00016. (A) The magnitude of CTL targeting (as determined by IFN-γ ELISpot using 53 pools of 16 or fewer overlapping peptides spanning the entire HIV-1 proteome) is plotted for subjects 00015 and 00016. The screening peptides were based on the clade B consensus sequence for Pol, Nef, Tat, Rev, Vpu, Vif, and Vpr; strain MN sequence for Env; and strain DU sequence for Gag. Subsequent screening with clade B consensus Gag sequences revealed similar results to strain DU (not shown). (B) The number of epitope regions (as determined by subsequent analysis of individual 15-mer peptides) is plotted for subjects 00015 and 00016.

FIG. 3.

Phylogenetic relationships of subjects 00015 and 00016 HIV-1 sequences to clade B consensus, NL4-3, and other primary isolates. Multiple cloned sequences from subjects 00015 and 00016 were compared to other contemporaneous primary isolate sequences, NL4-3, and Los Alamos National Laboratory HIV Sequence Database clade B consensus sequences. Neighbor-joining trees rooted on the clade B consensus sequence and evaluated with 1,000 bootstrap replicates are shown for gag (nucleotides 1232 to 1754 according to the HXB2 numbering system) and nef. Similar phylogenetic clustering relationships were observed for subject 00015 and 00016 pol and vif (not shown).

FIG. 4.

Phylogenetic divergence of gag, pol, and nef from subjects 00015 and 00016 versus clade B consensus sequences and intraindividual genetic diversity. Nucleotide sequences from subjects 00015 and 00016 and the Los Alamos HIV Database clade B consensus were assessed for divergence and diversity. The regions analyzed included nucleotides (HXB2 numbering) 1233 to 1755 (Gag amino acids 149 to 322), 2481 to 3019 (Pol amino acids 133 to 312), and 8797 to 9417 (Nef amino acids 1 to 207).