HIV-1 Viral Escape in Infancy Followed by Emergence of a Variant-Specific CTL Response

Abstract

Mutational escape from the CTL response represents a major driving force for viral diversification in HIV-1-infected adults, but escape during infancy has not been described previously. We studied the immune response of perinatally infected children to an epitope (B57-TW10) that is targeted early during acute HIV-1 infection in adults expressing HLA-B57 and rapidly mutates under this selection pressure. Viral sequencing revealed the universal presence of escape mutations within TW10 among B57- and B5801-positive children. Mutations in TW10 and other B57-restricted epitopes arose early following perinatal infection of B57-positive children born to B57-negative mothers. Surprisingly, the majority of B57/5801-positive children exhibited a robust response to the TW10 escape variant while recognizing the wild-type epitope weakly or not at all. These data demonstrate that children, even during the first years of life, are able to mount functional immune responses of sufficient potency to drive immune escape. Moreover, our data suggest that the consequences of immune escape may differ during infancy because most children mount a strong variant-specific immune response following escape, which is rarely seen in adults. Taken together, these findings indicate that the developing immune system of children may exhibit greater plasticity in responding to a continually evolving chronic viral infection.

Altering Effects of Antigenic Variations in HIV-1 on Antiviral Effectiveness of HIV-Specific CTLs

“…In our study, the ex vivo analysis of patients' PBMCs by HLA tetramers as well as IFN-␥ assays clearly showed the generation of CD8 T cells exclusively specific for the variant epitopes, indicating that original antigenic sin could be overcome in the case of some HLA-B*35-restricted epitopes. This finding is consistent with recent reports showing that, based on ex vivo analysis by IFN-␥ assays, the human immune system is capable of mounting novel CD8 T cell responses against CTL escape variants of Gag epitopes restricted by HLA-A*11 (29) and HLA-B*57 (30). However, considering that HLA-B*35 is an HLA class I allele associated with rapid disease progression while HLA-A*11 and HLA-B*57 are associated with slow disease progression (10,31), it is conceivable that the failure to generate functionally effective, variant-specific CTLs restricted by HLA-B*35, as observed in this study, could result in relatively insufficient virus containment by HLA-B*35-restricted CTL responses in vivo, leading to a consequent association between HLA-B*35 and rapid disease progression.…”

Dendritic cell based vaccines for HIV infection

“…It could be argued that HIV has already escaped to the immune system of the patient so boosting with the same virus will not improve the breadth of the immune response and would not be effective. However, although it is true that viral escape to CTL has been extensively demonstrated, [30][31][32][33] some data suggest that the antigen-presenting functions of dendritic cells are impaired in HIV-1 infected patients and this could contribute to the functional defects of HIV-1-specific helper and CTL responses. 34,35 We think that our model could help to know if a correct antigen presentation with this therapeutic vaccine could reverse the functional defect of helper and CTL responses and prevent, at least partially, the viral escape.…”

Clade-Specific Evolution Mediated by HLA-B*57/5801 in Human Immunodeficiency Virus Type 1 Clade A1 p24

“…Escape in this epitope usually occurs early in infection, which coincidently is when HLA-B*57 is most protective (18). In clade B and C infections, Ͼ75 to 100% of HLA-B*57/5801 ϩ subjects develop the T242N escape mutation, while HLA-B*57/5701-negative subjects rarely display polymorphism at this residue (5,9,10,15,32,35,38,41). When T242N is transmitted to HLA-B*57/5801-negative subjects, it rapidly reverts to the consensus, suggesting that T242N is associated with a fitness defect (32,35).…”