Abstract:Identification and characterization of CD8؉ T cells effectively controlling HIV-1 variants are necessary for the development of AIDS vaccines and for studies of AIDS pathogenesis, although such CD8 ؉ T cells have been only partially identified. In this study, we sought to identify CD8 ؉ T cells controlling HIV-1 variants in 401 Japanese individuals chronically infected with HIV-1 subtype B, in which protective alleles HLA-B*57 and HLA-B*27 are very rare, by using comprehensive and exhaustive methods. We identi… Show more
“…It is known that HLA-B*52:01-C*12:02 has a protective effect on the disease progression in HIV-1-infected Japanese individuals. Our recent study showed that HLA-B*52:01-restricted CTLs recognizing the five epitopes effectively suppress HIV-1 replication in the Japanese population (19). We showed here an additional mechanism for the protective effect of HLA-B*52:01-C*12:02 on the clinical outcome.…”
Section: Discussionmentioning
confidence: 71%
“…We therefore sought to identify such CTL epitopes. We first attempted to identify a CTL epitope containing Pol 68 by using 11-mer Pol overlapping peptides generated in a previous study (19). Since HLA-B*52:01-binding peptides have the Q2 anchor residue (35), we selected two 11-mer overlapping peptides, Pol 11 to 30 (Pol11-30; ITLWQRPLVTI) and Pol11-31 (LWQRPLVTIKI) as candidate peptides.…”
HLA-B*52:01-C*12:02, which is the most abundant haplotype in Japan, has a protective effect on disease progression in HIV-1-infected Japanese individuals, whereas HLA-B*57 and -B*27 protective alleles are very rare in Japan. A previous study on HLA-associated polymorphisms demonstrated that the number of HLA-B*52:01-associated mutations at four Pol positions was inversely correlated with plasma viral load (pVL) in HLA-B*52:01-negative individuals, suggesting that the transmission of HIV-1 with these mutations could modulate the pVL in the population. However, it remains unknown whether these mutations were selected by HLA-B*52:01-restricted CTLs and also reduced viral fitness. In this study, we identified two HLA-B*52:01-restricted and one HLA-C*12:02-restricted novel cytotoxic T-lymphocyte (CTL) epitopes in Pol. Analysis using CTLs specific for these three epitopes demonstrated that these CTLs failed to recognize mutant epitopes or more weakly recognized cells infected with mutant viruses than wild-type virus, supporting the idea that these mutations were selected by the HLA-B*52:01- or HLA-C*12:02-restricted T cells. We further showed that these mutations reduced viral fitness, although the effect of each mutation was weak. The present study demonstrated that the accumulation of these Pol mutations selected by HLA-B*52:01- or HLA-C*12:02-restricted CTLs impaired viral replication capacity and thus reduced the pVL. The fitness cost imposed by the mutations partially accounted for the effect of the HLA-B*52:01-C*12:02 haplotype on clinical outcome, together with the effect of HLA-B*52:01-restricted CTLs on viral replication, which had been previously demonstrated.
IMPORTANCE Numerous population-based studies identified HLA-associated HIV-1 mutations to predict HIV-1 escape mutations from cytotoxic T lymphocytes (CTLs). However, the majority of these HLA-associated mutations have not been identified as CTL escape mutations. Our previous population-based study showed that five HLA-B*52:01-associated mutations at four Pol positions were inversely correlated with the plasma viral load in HLA-B*52:01-negative Japanese individuals. In the present study, we demonstrated that these mutations were indeed selected by CTLs specific for novel B*52:01- and C*12:02-restricted epitopes and that the accumulation of these mutations reduced the viral fitness in vitro. This study elucidated the mechanism by which the accumulation of these CTL escape mutations contributed to the protective effect of the HLA-B*52:01-HLA-C*12:02 haplotype on disease progression in HIV-1-infected Japanese individuals.
“…It is known that HLA-B*52:01-C*12:02 has a protective effect on the disease progression in HIV-1-infected Japanese individuals. Our recent study showed that HLA-B*52:01-restricted CTLs recognizing the five epitopes effectively suppress HIV-1 replication in the Japanese population (19). We showed here an additional mechanism for the protective effect of HLA-B*52:01-C*12:02 on the clinical outcome.…”
Section: Discussionmentioning
confidence: 71%
“…We therefore sought to identify such CTL epitopes. We first attempted to identify a CTL epitope containing Pol 68 by using 11-mer Pol overlapping peptides generated in a previous study (19). Since HLA-B*52:01-binding peptides have the Q2 anchor residue (35), we selected two 11-mer overlapping peptides, Pol 11 to 30 (Pol11-30; ITLWQRPLVTI) and Pol11-31 (LWQRPLVTIKI) as candidate peptides.…”
HLA-B*52:01-C*12:02, which is the most abundant haplotype in Japan, has a protective effect on disease progression in HIV-1-infected Japanese individuals, whereas HLA-B*57 and -B*27 protective alleles are very rare in Japan. A previous study on HLA-associated polymorphisms demonstrated that the number of HLA-B*52:01-associated mutations at four Pol positions was inversely correlated with plasma viral load (pVL) in HLA-B*52:01-negative individuals, suggesting that the transmission of HIV-1 with these mutations could modulate the pVL in the population. However, it remains unknown whether these mutations were selected by HLA-B*52:01-restricted CTLs and also reduced viral fitness. In this study, we identified two HLA-B*52:01-restricted and one HLA-C*12:02-restricted novel cytotoxic T-lymphocyte (CTL) epitopes in Pol. Analysis using CTLs specific for these three epitopes demonstrated that these CTLs failed to recognize mutant epitopes or more weakly recognized cells infected with mutant viruses than wild-type virus, supporting the idea that these mutations were selected by the HLA-B*52:01- or HLA-C*12:02-restricted T cells. We further showed that these mutations reduced viral fitness, although the effect of each mutation was weak. The present study demonstrated that the accumulation of these Pol mutations selected by HLA-B*52:01- or HLA-C*12:02-restricted CTLs impaired viral replication capacity and thus reduced the pVL. The fitness cost imposed by the mutations partially accounted for the effect of the HLA-B*52:01-C*12:02 haplotype on clinical outcome, together with the effect of HLA-B*52:01-restricted CTLs on viral replication, which had been previously demonstrated.
IMPORTANCE Numerous population-based studies identified HLA-associated HIV-1 mutations to predict HIV-1 escape mutations from cytotoxic T lymphocytes (CTLs). However, the majority of these HLA-associated mutations have not been identified as CTL escape mutations. Our previous population-based study showed that five HLA-B*52:01-associated mutations at four Pol positions were inversely correlated with the plasma viral load in HLA-B*52:01-negative Japanese individuals. In the present study, we demonstrated that these mutations were indeed selected by CTLs specific for novel B*52:01- and C*12:02-restricted epitopes and that the accumulation of these mutations reduced the viral fitness in vitro. This study elucidated the mechanism by which the accumulation of these CTL escape mutations contributed to the protective effect of the HLA-B*52:01-HLA-C*12:02 haplotype on disease progression in HIV-1-infected Japanese individuals.
“…There is growing consensus that not all of the antiviral immune responses contribute to immune control of the virus and that some clones directed against conserved epitopes may efficiently mediate viral clearance (12,13). Limitation of immune activation might therefore contribute to viral load control.…”
Off-therapy control of viremia by HIV-infected individuals has been associated with two likely players: a restricted viral reservoir and an efficient cell-mediated immune response. We previously showed that a combination of highly suppressive antiretroviral therapy and two experimental drugs, i.e., auranofin and buthionine sulfoximine, was able to reduce the viral reservoir, elicit efficient cell-mediated antiviral responses, and induce intermittent posttherapy viral load control in chronically SIVmac251-infected macaques. We here show that the macaques that had received this drug combination and then stopped antiretroviral therapy were also able to maintain low numbers of activated CD4؉ T cells at viral rebound. Moreover, these macaques consistently displayed low-level simian immunodeficiency virus (SIV) diversity, which was in line with the strong and broadly reactive cell-mediated immune responses against conserved Gag antigens. Extended follow-up showed that the two macaques that had received the complete drug combination remained healthy and did not develop AIDS in 2 years of follow-up after therapy suspension. This disease-free survival is longer than twice the average time of progression to AIDS in SIVmac251-infected rhesus macaques. These results suggest that limited numbers of activated T cells at viral rebound and subsequent development of broadly reactive cell-mediated responses may be interrelated in reducing the viral reservoir.
IMPORTANCE
The HIV reservoir in CD4؉ T cells represents one main obstacle to HIV eradication. Recent studies, however, show that a drastic reduction of this reservoir is insufficient for inducing a functional cure of AIDS. In the present work, we thoroughly studied and subjected to long-term follow-up two macaques showing intermittent control of the virus following suspension of antiretroviral therapy plus an experimental antireservoir treatment, i.e., the gold salt auranofin and the investigational chemotherapeutic agent buthionione sulfoximine (BSO). We found that these drugs were able to decrease the number of activated CD4 ؉ T cells, which are preferential targets for HIV infection. Then, efficient immune responses against the virus were developed in the macaques, which remained healthy during 2 years of follow-up. This result may furnish another building block for future attempts to cure HIV/AIDS.
“…Note that in each immunogen, the individual regions are in different orders to avoid possible induction of strong, but irrelevant, responses to potential junctional epitopes.Figure 1Vaccines(A) tHIVconsvX immunogens (insets). The vaccines focus T cells on six highly functionally conserved regions of HIV-1 Gag and Pol proteins and their efficacy is enhanced by maximizing the vaccine match to global HIV-1 isolates through a computer-designed bivalent mosaic 47 and inclusion of beneficial epitopes 39, 40. For each immunogen tHIVconsv1-tHIVconsv6, the selected conserved regions are organized in different orders to avoid boosting of potential junctional epitopes.…”
Section: Resultsmentioning
confidence: 99%
“…More recently, we enhanced this conserved-region approach by replacing the consensus sequences with a bivalent mosaic design (tHIVconsvX, second generation), 34 which computationally increases as much as possible the match of candidate vaccines to the currently worldwide circulating HIV-1 variants for maximum effector efficacy 34, 35, 36, 37, 38. Furthermore, we adjusted the boundaries of conserved regions to cover the majority of conserved and, at the same time, beneficial CTL epitopes, which have been associated in HIV-1-positive, treatment-naive cohorts on four continents with low viral load and high CD4 + T cell count 34, 39, 40. Finally, each of the six tHIVconsvX immunogens tHIVconsv1–tHIVconsv6 has the six conserved regions organized in a unique order to minimize induction of T cell responses to junctions, which are not present in the HIV-1 proteome and are, therefore, an avoidable distraction to the immune response 34 …”
To be effective against HIV type 1 (HIV-1), vaccine-induced T cells must selectively target epitopes, which are functionally conserved (present in the majority of currently circulating and reactivated HIV-1 strains) and, at the same time, beneficial (responses to which are associated with better clinical status and control of HIV-1 replication), and rapidly reach protective frequencies upon exposure to the virus. Heterologous prime-boost regimens using virally vectored vaccines are currently the most promising vaccine strategies; nevertheless, induction of robust long-term memory remains challenging. To this end, lentiviral vectors induce high frequencies of memory cells due to their low-inflammatory nature, while typically inducing only low anti-vector immune responses. Here, we describe construction of novel candidate vaccines ZVex.tHIVconsv1 and ZVex.tHIVconsv2, which are based on an integration-deficient lentiviral vector platform with preferential transduction of human dendritic cells and express a bivalent mosaic of conserved-region T cell immunogens with a high global HIV-1 match. Each of the two mosaic vaccines was individually immunogenic. When administered together in heterologous prime-boost regimens with chimpanzee adenovirus and/or poxvirus modified vaccinia virus Ankara (MVA) vaccines to BALB/c and outbred CD1-Swiss mice, they induced a median frequency of over 6,000 T cells/106 splenocytes, which were plurifunctional, broadly specific, and cross-reactive. These results support further development of this vaccine concept.
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