Maternal HIV-1 envelope–specific antibody responses and reduced risk of perinatal transmission

Despite the wide availability of antiretroviral drugs, more than 250,000 infantsare vertically infected with HIV-1 annually, emphasizing the need for additionalinterventions to eliminate pediatric HIV-1 infections. Here, we aimed to definehumoral immune correlates of risk of mother-to-child transmission (MTCT) ofHIV-1, including responses associated with protection in the RV144 vaccinetrial. Eighty-three untreated, HIV-1–transmitting mothers and 165 propensityscore–matched nontransmitting mothers were selected from the Women and InfantsTransmission Study (WITS) of US nonbreastfeeding, HIV-1–infected mothers. In amultivariable logistic regression model, the magnitude of the maternal IgGresponses specific for the third variable loop (V3) of the HIV-1 envelope waspredictive of a reduced risk of MTCT. Neutralizing Ab responses againsteasy-to-neutralize (tier 1) HIV-1 strains also predicted a reduced risk ofperipartum transmission in secondary analyses. Moreover, recombinant maternalV3–specific IgG mAbs mediated neutralization of autologous HIV-1 isolates. Thus,common V3-specific Ab responses in maternal plasma predicted a reduced risk ofMTCT and mediated autologous virus neutralization, suggesting that boostingthese maternal Ab responses may further reduce HIV-1 MTCT.     

Prevalence of dihydropteroate synthase genotypes before and after the introduction of combined antiretroviral therapy and their influence on the outcome of Pneumocystis pneumonia in HIV-1–infected patients

The objective of this study was to determine whether the prevalence of Pneumocystis jirovecii dihydropteroate synthase (DHPS) gene mutations has changed since the introduction of combined antiretroviral therapy (cART) and whether the mutations are associated with poor outcome in Spanish HIV-1–infected patients with Pneumocystis pneumonia (PcP). We studied 167 PcP episodes in HIV-1–infected patients diagnosed during the pre-cART (1989–1995) and cART (2001–2004) periods. Molecular genotyping of DHPS was successfully performed in 98 patients (43 pre-cART and 55 cART). Seventeen patients (17/98, 17%; 95% confidence interval [CI], 10–25%) had mutations in the DHPS gene: 14 patients (14/43, 33%; 95% CI, 19–49%) from the pre-cART period and 3 patients (3/55, 5.5%; 95% CI, 1.3–16%) from the cART period (P < 0.01). In the multivariate analysis, the pre-cART period, previous PcP prophylaxis with sulfa drugs, and homosexuality as an HIV risk factor were found to be associated with a higher risk of presenting DHPS mutations. Overall, 95% of patients were treated with trimethoprim and sulfamethoxazole (TMP–SMX). In-hospital mortality was similar in patients with (out) mutations (6% versus 11%, P = 0.84). DHPS gene mutations were more common during the pre-cART period and were associated with previous sulfa exposure and homosexuality. However, their presence did not worsen prognosis of PcP. The response to TMP–SMX with therapeutic doses was successful in most cases.     

Persistence of pandemic influenza H1N1 virus in young patients after oseltamivir therapy in the 2009–2010 season: a comparison with seasonal H1N1 with or without H275Y mutation

Comparison of the viral persistence of pandemic H1N1 (H1N1pdm) and seasonal H1N1 with or without H275Y mutation after oseltamivir therapy has not been adequately done. Virus was isolated before and on days 4-6 from the start of oseltamivir treatment for 158 cases of seasonal (2007-2008 and 2008-2009 seasons) or pandemic (2009-2010 season) H1N1 influenza. Sequence analysis was done for each season and NA inhibition assay (IC(50)) was done in the 2009-2010 season. H275Y mutation before therapy was 0% in the 2007-2008 and 2009-2010 seasons, but 100% in the 2008-2009 season. Fever and other symptoms were noticeably prolonged after oseltamivir therapy for children with H275Y mutated seasonal H1N1 (2008-2009 season), but not in patients with seasonal H1N1 without mutation (2007-2008) or H1N1pdm (2009-2010). The viral persistence rate was significantly higher for patients 15 years or younger than for those 16 years and older with H275Y mutated seasonal H1N1 (46.2% and 10.5%, respectively) or with H1N1pdm (43.3% and 11.5%, respectively). The H275Y mutation emerged after oseltamivir treatment in 2.4% (2/82) of all patients with H1N1pdm. In two children, the H275Y mutation emerged after therapy and the IC(50) increased more than 200 fold; however, the prolongation of fever was not so prominent. In conclusion, oseltamivir was effective for fever and other clinical symptoms; however, the virus persisted longer than expected after treatment in H1N1pdm influenza-infected children in the 2009-2010 season, similar to seasonal H1N1 with H275Y mutation in the 2008-2009 season.     

Misunderstanding of hepatitis C virus (HCV) infection status by non–specialized medical doctors in patients who achieved sustained virologic response to anti-HCV therapy

IntroductionWith the increase in the number of patients with sustained virologic response (SVR) in whom hepatitis C virus (HCV) was eradicated by the anti-HCV therapy, there are now many individuals in whom serum HCV RNA is absent despite positive serum HCV antibodies. However, in general clinical practice, HCV infection remains usually screened by measurement of serum HCV antibodies and patients with SVR can be misunderstood regarding HCV infection status.MethodsIn the multicenter study, we conducted interviews with administered questionnaires to SVR individuals who had regular hospital visits after SVR. The prevalence of experiencing an incorrect diagnosis of HCV infection after SVR was assessed. Individuals who experienced this misunderstanding were further asked where they experienced it and how it made them feel.ResultsIn a survey of 2,246 SVR individuals, 197 individuals (8.8%) were misunderstood as having persistent HCV infection by medical doctors due to positive HCV antibody, despite the absence of HCV viremia. These misunderstandings occurred most prevalently at a private clinic (55.3%). More than half (53.3%) of these individuals felt anxious about their HCV infection with becoming unsure about their HCV eradication status.ConclusionsMisunderstanding HCV status is commonly occurred in SVR individuals. Specialists in hepatology and infectious diseases should broadly emphasize the fact that most patients with HCV antibodies are now HCV-free because of the use of anti-HCV therapy.     

Patterns of Immunodominance in HIV-1–specific Cytotoxic T Lymphocyte Responses in Two Human Histocompatibility Leukocyte Antigens (HLA)-identical Siblings with HLA-A*0201 Are Influenced by Epitope Mutation

Primary human immunodeficiency virus (HIV) infection is controlled principally by HIV-specific cytotoxic T lymphocytes (CTL) to a steady-state level of virus load, which strongly influences the ultimate rate of progression to disease. Epitope selection by CTL may be an important determinant of the degree of immune control over the virus. This report describes the CTL responses of two HLA-identical hemophiliac brothers who were exposed to identical batches of Factor VIII and became seropositive within 10 wk of one another. Both have HLA-A*0201. The CTL responses of the two siblings were very dissimilar, one donor making strong responses to two epitopes within p17 Gag (HLA-A*0201–restricted SLYNTVATL and HLA-A3–restricted RLRPGGKKK). The sibling responded to neither epitope, but made strong responses to two epitopes presented by HLA-B7. This was not the result of differences in presentation of the epitopes. However, mutations in both immunodominant epitopes of the p17 Gag responder were seen in proviral sequences of the nonresponder. We then documented the CTL responses to two HLA-A*0201–restricted epitopes, in Gag (SLYNTVATL) and Pol (ILKEPVHGV) in 22 other HIV-infected donors with HLA-A*0201. The majority (71%) generated responses to the Gag epitope. In the 29% of donors failing to respond to the Gag epitope in standard assays, there was evidence of low frequency memory CTL responses using peptide stimulation of PBMC, and most of these donors also showed mutations in or around the Gag epitope. We concluded that HLA class I genotype determines epitope selection initially but that mutation in immunodominant epitopes can profoundly alter the pattern of CTL response.CTLs play a central role in the immune response to virus infections (1–4). In HIV infection, CTLs are responsible for the clearance of viremia after primary infection (5–6), and there is strong evidence that they also contribute to prolongation of the disease-free phase of infection (7–10). However, it is not possible to distinguish slow progressors from rapid progressors on the basis of CTL precursor frequency during this asymptomatic phase of infection (9). One explanation is that CTL responses may differ qualitatively. Responses directed at more conserved regions of the virus may be qualitatively superior, because there is less scope for CTL escape mutation to occur without simultaneously damaging the fitness of the virus itself.Support for qualitative differences in CTL responses derives from studies of HLA associations with rate of progression in HIV infection. HLA class I molecules such as HLAB27, HLA-B57, and HLA-B51 have been linked with slow progression, while HLA-B8 and HLA-B35 have been associated with rapid development of disease in several studies (11–13). In one study of slow progressors with HLA-B57, all seven donors tested made the immunodominant response through HLA-B57 rather than any other of their class I molecules (14).The strong influence of the HLA class I genotype of an individual upon the selection of HIV-specific immunodominant epitopes has been observed for HLA-B27 (10), HLA-B14 (15), and many other examples in other virus infections, for example HLA-A11–restricted Epstein–Barr virus–specific responses (16). In general, patients with a given HLA type react to HIV epitopes in a predictable way (17). Particular MHC molecules may be associated with slow progression because, by chance, the immunodominant epitopes selected are relatively invariant. Switching an individual''s immunodominant response away from a variable region of the virus towards a highly conserved region might prove to be a valuable therapeutic option.It is not known what determines the immunodominance of an individual''s CTL response. Possible selective events include specificity of the proteases (18–19), TAP (antigen processing-associated transporter)-dependent transport into the endoplasmic reticulum (20–21), binding affinities of peptides to class I molecules (22), and the stability of peptide–MHC complexes on the cell surface (16, 23). Also, the T cell repertoires may contribute significantly. Some CTL responses to dominant epitopes are oligoclonal, with very similar or even identical TCRs used in different individuals, implying selection among the T cells used by particular epitopes (24–26).We have studied two HLA-identical hemophiliac siblings within a cohort of HIV-infected donors who have HLA-A*0201. These brothers first tested seropositive within 10 wk of one another in 1983 and 1984, as a result of exposure to an identical batch of HIV-contaminated Factor VIII concentrate. The CTL responses of these HLA-identical siblings are substantially different, correlating with the presence of striking epitope mutations within the provirus of the nonresponder.The CTL response of these and 22 other HLA-A*0201– positive individuals to two well-defined HLA-A*0201– restricted epitopes, SLYNTVATL (p17 Gag, HIV-1 LAI residues 77–85 [27]) and ILKEPVHGV (Pol, residues 476–484 [28]) has been plotted. The majority of donors generate dominant responses to the Gag epitope, a minority prefer the Pol epitope, and most of this latter group show mutations in or around the Gag epitope.