Cross-Clade-Specific Cytotoxic T Lymphocytes in HIV-1-Infected Children

Abstract

We studied cytotoxic T lymphocyte (CTL) cross-reactivity between human immunodeficiency virus type 1 (HIV-1) subtypes within a group of infants infected with either HIV-1 B or non-B clade. Fifteen children were infected with a clade B virus. Nine were infected with non-B virus, including two clade A, four clade D, two clade F, and one clade G. CTL activities from in vitro activated peripheral blood mononuclear cells were tested against autologous cell line infected with recombinant vaccinia viruses encoding for Env, Gag, Pol, or Nef proteins from a clade A or B isolate. HIV-1-specific CTL elicited from infection with clade B virus could lyse targets expressing clade A proteins, and vice versa. In infants with positive CTL responses, cross-clade recognition was predominant and was detected within 88% of the Pol, 83% of the Nef, 67% of the Gag, and 55% of the Env responders. Longitudinal studies showed that CTL cross-reactivity to both B and A targets was stable for several years. Elicitation of CTL reactivities capable of elimination of virus-infected cells is an important goal for the development of an efficient AIDS vaccine. The significant cross-reactivity of CTL shown in this study supports the concept that vaccines developed using a single-clade immunogen may be applicable to induce broadly reactive T cell responses.

Comprehensive Screening Reveals Strong and Broadly Directed Human Immunodeficiency Virus Type 1-Specific CD8 Responses in Perinatally Infected Children

“…Early studies of the HIV-1-specific CTL response among perinatally infected children indicated that these responses emerge later and are generally weaker and narrower than in their adult counterparts (9,11,25,26,30,38,40). However, these studies relied on techniques that are less sensitive than those currently available and that provide no information about the epitopes targeted or the overall breadth of response.…”

Patient-Specific Cytotoxic T-Lymphocyte Cross-Recognition of Naturally Occurring Variants of a Human Immunodeficiency Virus Type 1 (HIV-1) p24gagEpitope by HIV-1-Infected Children

“…Seven children included in a longitudinal follow-up study of their CTL activities were selected for their expression of HLA-B53 or -B57, as determined by amplification refractory mutation system PCR (4,5). Peripheral blood mononuclear cell (PBMC) samples exhibiting significant lysis against the HIV p55 gag protein were chosen for this study.…”

“…Mother-to-child transmission of HIV was responsible for infection of the other children. Their infecting subtypes were determined by heteroduplex mobility assay or sequencing of the Env gene, as previously reported (5). Patients' clinical and biological characteristics are summarized in Table 1.…”

Induction of long‐lasting multi‐specific CD8+ T cells by a four‐component DNA‐MVA/HIVA‐RENTA candidate HIV‐1 vaccine in rhesus macaques

“…The extent of CD8 + T cell cross-reactivity remains controversial with evidence both for [10][11][12][13][14][15][16][17] and against [18][19][20][21][22] its broad effectiveness. At least in the one animal tested on two occasions, we observed cross-reactivity of CD8 + T cells with 50% of tested epitope variants not present in the vaccine (Fig.…”

“…A number of studies have addressed this point with mixed results. While some studies clearly detected cross-clade-reactive HIV-1-specific CD8 + T cell responses [10][11][12][13][14][15][16][17], there is substantial evidence that CD8 + T cells can be highly sequence-specific [18][19][20][21][22]. This was best demonstrated in systematic studies employing all possible single amino acid substitutions in each position of an MHC class I epitope, which suggested that as few as one in three epitope variants was recognized by a given T cell receptor [18,23].…”