Transmission of HIV-1 CTL escape variants provides HLA-mismatched recipients with a survival advantage

Abstract

One of the most important genetic factors known to affect the rate of disease progression in HIV-infected individuals is the genotype at the Class I Human Leukocyte Antigen (HLA) locus, which determines the HIV peptides targeted by cytotoxic T-lymphocytes (CTLs). Individuals with HLA-B*57 or B*5801 alleles, for example, target functionally important parts of the Gag protein. Mutants that escape these CTL responses may have lower fitness than the wild-type and can be associated with slower disease progression. Transmission of the escape variant to individuals without these HLA alleles is associated with rapid reversion to wild-type. However, the question of whether infection with an escape mutant offers an advantage to newly infected hosts has not been addressed. Here we investigate the relationship between the genotypes of transmitted viruses and prognostic markers of disease progression and show that infection with HLA-B*57/B*5801 escape mutants is associated with lower viral load and higher CD4+ counts.

Figure 1. The accumulation of non-synonymous mutations within the three B57/B5801-specific immunodominant epitopes.

Comparison of the odds ratio of non-synonymous mutations within TW10, ISW9 and KF11 between those B57/B5801-negative participants infected with variants carrying the T242N and A146X mutations and those not carrying the mutations.

Figure 2. Sequence alignment of ISW9, KF11 and TW10 epitopes.

Sequence changes of the 9 participants carrying the T242N and A146X mutations in B57/B5801-specific immunodominant epitopes over time showing reversion to consensus sequence at position 242. One flanking amino acid residue was included on either side of the epitope. The position of the H219Q compensatory mutation is indicated relative to the epitopes. MO. PI refers to months post-infection.

Figure 3. Proportion of HLA-B*57/5801-associated escape mutations at different time-points.

Gag bulk PCR products were cloned and sequenced at three available timepoints as indicated on the x-axis. A median of 12 sequences (range 7–20) were analyzed per participant per time-point.

Figure 4. A) Viral load and B) CD4+ counts over time for the 6 participants infected with virus carrying the T242N mutation at enrolment.

The amino acid residue at position 242 is indicated for the time-points cloned and sequenced. Red squares indicate N242 and blue squares indicate T242. Where there was more than one variant, the dominant residue is shown in upper case whereas lower case letters indicate the subdominant residues.

Figure 5. Mean and standard error of A) log viral loads and B) CD4+ counts over a 15 month period for the 21 study participants.

The T242N/A146X+ participants are shown in red and the T242N/a146X- participants are shown in blue.

Figure 6. Viral Load and CD4+ counts of study participants grouped according to the presence or absence of the T242N and/or A146X mutations at enrolment.

The 21 B57/B5801 negative individuals were grouped into those infected with viral strains comprising both the TW10 escape mutation and the ISW9 processing escape mutation (n = 9) and those that did not (n = 12). The viral load and CD4+ counts at 3 and 12 months post-infection were compared between these two groups. HLA-B*5801 positive individuals were excluded from the analysis. ▴ denotes viral loads and CD4+ counts for the two individuals infected with viruses carrying the H219Q compensatory mutation.