Defining the antiviral efficacy of CD8 T cells is important for immunogen design

Human immunodeficiency virus type 1 (HIV-1)-specific CD8؉ T cells in early infection are associated with the dramatic decline of peak viremia, whereas their antiviral activity in chronic infection is less apparent. The functional properties accounting for the antiviral activity of HIV-1-specific CD8 ؉ T cells during early infection are unclear. Using cytokine secretion and tetramer decay assays, we demonstrated in intraindividual comparisons that the functional avidity of HIV-1-specific CD8 ؉ T cells was consistently higher in early infection than in chronic infection in the presence of high-level viral replication. This change of HIV-1-specific CD8 ؉ T-cell avidity between early and chronic infections was linked to a substantial switch in the clonotypic composition of epitope-specific CD8 ؉ T cells, resulting from the preferential loss of high-avidity CD8 ؉ T-cell clones. In contrast, the maintenance of the initially recruited clonotypic pattern of HIV-1-specific CD8 ؉ T cells was associated with low-level set point HIV-1 viremia. These data suggest that high-avidity HIV-1-specific CD8 ؉ T-cell clones are recruited during early infection but are subsequently lost in the presence of persistent high-level viral replication.

Chronic inflammation is a hallmark of HIV infection and is associated with the development and progression of age-related comorbidities. Although the gastrointestinal tract is a major site of HIV replication and CD4 + T-cell depletion, the role of HIV-associated imbalance of gut microbiome in chronic inflammation is unclear.

Japan has been known as a low HIV-prevalence country with a concentrated epidemic among high-risk groups. However, it has not been determined whether Japan meets the 90-90-90 goals set by the Joint United Nations Programme on HIV/AIDS (UNAIDS)/World Health Organization (WHO). Moreover, to date, the HIV care cascade has not been examined. We estimated the total number of diagnosed people living with HIV/AIDS (PLWHA) (n = 22,840) based on legal reports to the Ministry of Health, Labour and Welfare by subtracting the number of foreigners who left Japan (n = 2,273) and deaths (n = 2,321) from the cumulative diagnosis report (n = 27,434). The number of total undiagnosed PLWHA was estimated by age and sex specific HIV-positive rates observed among first-time blood donors between 2011–2015 in Japan. Our estimates show that 14.4% (n = 3,830) of all PLWHA (n = 26,670) were undiagnosed in Japan at the end of 2015. The number of patients retained in care (n = 20,615: 77.3% of PLWHA), the percentage of those on antiretroviral therapy (n = 18,921: 70.9% of PLWHA) and those with suppressed viral loads (<200 copies/mL; n = 18,756: 70.3% of PLWHA) were obtained through a questionnaire survey conducted in the AIDS Core Hospitals throughout the country. According to these estimates, Japan failed to achieve the first two of the three UNAIDS/WHO targets (22,840/26,670 = 85.6% of HIV-positive cases were diagnosed; 18,921/22,840 = 82.8% of those diagnosed were treated; 18,756/18,921 = 99.1% of those treated experienced viral suppression). Although the antiretroviral treatment uptake and success after retention in medical care appears to be excellent in Japan, there are unmet needs, mainly at the surveillance level before patients are retained in care. The promotion of HIV testing and treatment programs among the key affected populations (especially men who have sex with men) may contribute to further decreasing the HIV epidemic and achieving the UNAIDS/WHO targets in Japan.

Hepatitis B virus (HBV) has seven genotypes, A to G. Previous studies have shown that genotype C is the most prevalent strain in chronic HBV carriers in East Asia. This study was undertaken to investigate the epidemiology of HBV genotypes among Japanese patients who are coinfected with human immunodeficiency virus type 1 (HIV-1). The sequences of the complete hepatitis B surface antifen (HBsAg) genes were obtained from 18 coinfected Japanese patients. Among the 18 patients, 12 of 13 men who had sex with men (MSM) had genotype A (92%), whereas only one of five heterosexual or hemophiliac patients had genotype A. The predominance of genotype A HBV in MSM showed a striking contrast to the current genotype prevalence in the Japanese population. Owing to the recent decrease in the rate of vertical transmission in Japan, the role of sexual behavior in the transmission of HBV cannot be overestimated. Thus, the relative proportion of genotype A may gradually increase in Japan.

Studies in acute human immunodeficiency virus type 1 (HIV-1) infection indicate viral evolution under CD8T-cell immune selection pressure, but the effects of ongoing immune pressure on epitope evolution during chronic infection are not well described. In this study, we performed a detailed longitudinal analysis of viral sequence variation within persistently targeted cytotoxic T-lymphocyte (CTL) epitopes in two HIV-1-infected persons during 6 years of persistent viremia. Responses were quantitated using freshly isolated peripheral blood lymphocytes in direct lytic assays as well as by gamma interferon (IFN-␥) Elispot assays on cryopreserved cells. Seven targeted epitopes were identified in each person. In the majority of cases, the dominant epitope sequence did not change over time, even in the presence of responses of sufficient magnitude that they were detectable using fresh peripheral blood mononuclear cells in direct lytic assays. Only 4 of the 14 autologous epitopes tested represented potential CTL escape variants; however, in most cases strong responses to these epitopes persisted for the 6 years of study. Although persistent IFN-␥ responses were detected to all epitopes, direct lytic assays demonstrated declining responses to some epitopes despite the persistence of the targeted sequence in vivo. These data indicate limited viral evolution within persistently targeted CD8 T-cell epitopes during the chronic phase of infection and suggest that these regions of the virus are either refractory to sequence change or that persistently activated CD8 T-cell responses in chronic infection exert little functional selection pressure.

The molecular mechanisms for IL2 gene-specific dysregulation during chronic human immunodeficiency virus type 1 (HIV-1) infection are unknown. Here, we investigated the role of DNA methylation in suppressing interleukin 2 (IL-2) expression in memory CD4(+) T cells during chronic HIV-1 infection. We observed that CpG sites in the IL2 promoter of CD4(+) T cells were fully methylated in naive CD4(+) T cells and significantly demethylated in the memory populations. Interestingly, we found that the memory cells that had a terminally differentiated phenotype and expressed CD57 had increased IL2 promoter methylation relative to less differentiated memory cells in healthy individuals. Importantly, early effector memory subsets from HIV-1-infected subjects expressed high levels of CD57 and were highly methylated at the IL2 locus. Furthermore, the increased CD57 expression on memory CD4(+) T cells was inversely correlated with IL-2 production. These data suggest that DNA methylation at the IL2 locus in CD4(+) T cells is coupled to immunosenescence and plays a critical role in the broad dysfunction that occurs in polyclonal T cells during HIV-1 infection.

The major routes of hepatitis B virus (HBV) infection inThe narrow genetic diversity in genotype A cases suggests that genotype A has been recently introduced into the MSM population and that sexual contacts among MSM were more active than speculated from HIV-1 tree analyses. In addition, we found a lamivudine resistance mutation in one naïve case, suggesting a risk of drug-resistant HBV transmission. As genotype A infection has a higher risk than infection with other genotypes for individuals to become HBV carriers, prevention programs are urgently needed for the target population.