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Background Calculated globulin fraction is derived from the liver function tests by subtracting albumin from the total protein. Since immunoglobulins comprise the largest component of the serum globulin concentration, increased or decreased calculated globulins and may identify patients with hypogammaglobulinaemia or hypergammaglobulinaemia, respectively. Methods A retrospective study of laboratory data over 2.5 years from inpatients at three tertiary hospitals was performed. Patients with paired calculated globulins and immunoglobulin results were identified and clinical details reviewed. The results of serum electrophoresis testing were also assessed where available. Results A total of 4035 patients had paired laboratory data available. A calculated globulin ≤20 g/L (4th percentile) were seen in patients with either liver disease (37%), haematological malignancy (36%), autoimmune disease (13%) or infections (9%). Conclusions Calculated globulin is an inexpensive and easily available test that assists in the identification of hypogammaglobulinaemia or hypergammaglobulinaemia which may prompt further investigation and reduce diagnostic delays.

Abacavir administration is associated with drug-induced hypersensitivity reactions in HIV+ individuals expressing the HLA-B*57:01 allele. However, the immunological effects of abacavir administration in an HLA-B57 mismatched transplantation setting have not been studied. We hypothesized that abacavir exposure could induce de novo HLA-B57-specific allorecognition. HIV-specific CD8 T cell clones were generated from HIV+ individuals, using single cell sorting based on HIV peptide/HLA tetramer staining. The T cell clones were assayed for alloreactivity against a panel of single HLA-expressing cell lines, in the presence or absence of abacavir. Cytokine assay, CD137 upregulation, and cytotoxicity were used as readout. Abacavir exposure can induce de novo HLA-B57 allorecognition by HIV-specific T cells. A HIV Gag RK9/HLA-A3-specific T cell did exhibit interferon-gamma production, CD137 upregulation, and cytolytic effector function against allogeneic HLA-B57, but only in the presence of abacavir. Allorecognition was specific to the virus specificity, HLA restriction, and T cell receptor TRBV use of the T cell. We provide proof-of-principle evidence that administration of a drug could induce specific allorecognition of mismatched HLA molecules in the transplant setting. We suggest that HIV-seropositive recipients of an HLA-B57 mismatched graft should not receive abacavir until further studies are completed.

The role of autoantibody testing for patients with interstitial lung disease is an evolving area. Recent guidelines recommend routine anti-nuclear antibodies, rheumatoid factor, and anti-citrullinated cyclic peptide antibody testing for patients undergoing diagnostic evaluation for interstitial lung disease, with further autoantibody testing reserved for selected cases guided by rheumatological features. Even this approach may miss patients with clinically significant autoantibodies when interstitial lung disease is the dominant or first manifestation of autoimmune disease. We retrospectively performed autoimmune serology in a clinically well characterised cohort of interstitial lung disease patients. Using stored serum, additional testing was performed to ensure all patients had complete autoantibody profiles including anti-nuclear antibodies, extractable nuclear antigen antibodies, double-stranded DNA antibodies, rheumatoid factor, anti-citrullinated cyclic peptide antibodies, anti-neutrophil cytoplasmic antibodies, and myositis antibodies. Eighty patients with interstitial lung disease, and available stored serum, were assessed. Mean age at interstitial lung disease diagnosis was 65.2 years and 42 patients were male. Positive autoimmune serology was found in 56 of 80 (70.0%) patients; the most common positive result was anti-nuclear antibodies (n=34; 42.5%). Myositis antibodies were detected in 13 of 80 (16.2%) patients. Four (5%) patients had elevated anti-citrullinated cyclic peptide antibodies, and two (2.5%) patients had detectable myeloperoxidase antibodies. Eleven (13.7%) patients with negative anti-nuclear antibodies had other significant disease associated autoantibodies. An extended panel of autoantibody testing may detect cases of connective tissue disease associated interstitial lung disease, regardless of clinical or radiological subtype, and prior to extra-pulmonary manifestations of systemic autoimmunity.

PURPOSE OF REVIEW: To summarize recent advances in our understanding of HIV adaptation to Human Leukocyte Antigen (HLA)-associated immune pressures, and its relevance to HIV prevention and cure research. RECENT FINDINGS: Recent research has confirmed that HLA is a major driver of individual- and population-level HIV evolution, that HIV strains are adapting to the immunogenetic profiles of the different human ethnic groups in which they circulate, and that HIV adaptation has substantial clinical and immunologic consequences. As such, adaptation represents a major challenge to HIV prevention and cure. At the same time, there are opportunities: Studies of HIV adaptation are revealing why certain HLA alleles are protective in some populations and not others; they are identifying immunogenic viral epitopes that harbor high mutational barriers to escape, and they may help illuminate novel, vaccine-relevant HIV epitopes in regions where circulating adaptation is extensive. Elucidation of HLA-driven adapted and nonadapted viral forms in different human populations and HIV subtypes also renders “personalized” immunogen selection, as a component of HIV cure strategies, conceptually feasible. SUMMARY: Though adaptation represents a major challenge to HIV prevention and cure, achieving an in-depth understanding of this phenomenon can help move the design of such strategies forward.

With the advent of next-generation sequencing (NGS), monogenic forms of common variable immunodeficiency (CVID) have been increasingly described. Our study aimed to identify disease-causing variants in a Western Australian CVID cohort using a novel targeted NGS panel. Targeted amplicon NGS was performed on 22 unrelated subjects who met the formal European Society for Immunodeficiencies-Pan-American Group for Immunodeficiency diagnostic criteria for CVID and had at least one of the following additional criteria: disease onset at age18 years, autoimmunity, low memory B lymphocytes, family history, and/or history of lymphoproliferation. Candidate variants were assessed by in silico predictions of deleteriousness, comparison to the literature, and classified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology criteria. All detected genetic variants were verified independently by an external laboratory, and additional functional studies were performed if required. Pathogenic or likely pathogenic variants were detected in 6 of 22 (27%) patients. Monoallelic variants of uncertain significance were also identified in a further 4 of 22 patients (18%). Pathogenic variants, likely pathogenic variants, or variants of uncertain significance were found in TNFRSF13B, TNFRSF13C, ICOS, AICDA, IL21R, NFKB2, and CD40LG, including novel variants and variants with unexpected inheritance pattern. Targeted amplicon NGS is an effective tool to identify monogenic disease-causing variants in CVID, and is comparable or superior to other NGS methods. Moreover, targeted amplicon NGS identified patients who may benefit from targeted therapeutic strategies and had important implications for family members.

The adjacent amino acid polymorphisms in the nucleocapsid (R203K/G204R) of SARS-CoV-2 arose on the background of the spike D614G change and strains harboring these changes have become dominant circulating strains globally. Sequence analysis suggests that the three adjacent nucleotide changes that result in the K203/R204 variant have arisen by homologous recombination from the core sequence (CS) of the leader transcription-regulating sequence (TRS) as opposed to a step-wise mutation model. The resulting sequence changes generate a novel sub-genomic RNA transcript for the C-terminal dimerization domain. Deep sequencing data from 981 clinical samples confirmed the presence of the novel TRS-CS-dimerization domain RNA in individuals with the K203/R204 variant. Quantification of sub-genomic RNA indicates that viruses with the K203/R204 variant may also have increased expression of sub-genomic RNA from other open reading frames. The K203/R204 variant results in a novel sub-genomic RNA. The finding that homologous recombination from the TRS may have occurred since the introduction of SARS-CoV-2 in humans resulting in both coding changes and novel sub-genomic RNA transcripts suggests this as a mechanism for diversification and adaptation within its new host. IMPORTANCE: A major variant of the SARS-CoV-2 virus (R203K/G204R in the nucleocapsid) results in changes to the nucleocapsid at both the protein and RNA level. We show this variant likely arose by homologous recombination from the core sequence of the leader transcription-regulating sequence (TRS) elsewhere in the viral genome. This recombination event introduced a new TRS between the RNA binding and dimerization domains of nucleocapsid that generates a novel sub-genomic RNA transcript. Presence of the K203/R204 variant was significantly associated with increased expression of nucleocapsid and sub-genomic RNA from other open reading frames. The mechanism by which the virus generates diversity, specifically how this KR variant arose and how it generated a novel major sub-genomic transcript is relevant to how future major shifts may arise and their potential functional implications.

Ceramides are central intermediates of sphingolipid metabolism with dual roles as mediators of cellular stress signaling and mitochondrial apoptosis. How ceramides exert their cytotoxic effects is unclear and their poor solubility in water hampers a search for specific protein interaction partners. Here, we report the application of a photoactivatable and clickable ceramide analog, pacCer, to identify ceramide binding proteins and unravel the structural basis by which these proteins recognize ceramide. Besides capturing ceramide transfer protein (CERT) from a complex proteome, our approach yielded CERT-related steroidogenic acute regulatory protein D7 (StarD7) as novel ceramide binding protein. Previous work revealed that StarD7 is required for efficient mitochondrial import of phosphatidylcholine (PC) and serves a critical role in mitochondrial function and morphology. Combining site-directed mutagenesis and photoaffinity labeling experiments, we demonstrate that the steroidogenic acute regulatory transfer domain of StarD7 harbors a common binding site for PC and ceramide. While StarD7 lacks robust ceramide transfer activity in vitro, we find that its ability to shuttle PC between model membranes is specifically affected by ceramides. Besides demonstrating the suitability of pacCer as a tool to hunt for ceramide binding proteins, our data point at StarD7 as a candidate effector protein by which ceramides may exert part of their mitochondria-mediated cytotoxic effects.

Objective: Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B*18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B*18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP. Methods: We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission. Results: Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B*18-positive individuals globally (P = 3.5 × 10−20) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B*18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10−4) and in unlinked HIV/HLA data from 43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub-Saharan Africa, Southeastern Europe) where B*18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time. Conclusions: Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP.

Human immunodeficiency virus (HIV) can adapt to an individual’s T cell immune response via genomic mutations that affect antigen recognition and impact disease outcome. These viral adaptations are specific to the host’s human leucocyte antigen (HLA) alleles, as these molecules determine which peptides are presented to T cells. As HLA molecules are highly polymorphic at the population level, horizontal transmission events are most commonly between HLA-mismatched donor/recipient pairs, representing new immune selection environments for the transmitted virus. In this study, we utilised a deep sequencing approach to determine the HIV quasispecies in 26 mother-to-child transmission pairs where the potential for founder viruses to be pre-adapted is high due to the pairs being haplo-identical at HLA loci. This scenario allowed the assessment of specific HIV adaptations following transmission in either a non-selective immune environment, due to recipient HLA mismatched to original selecting HLA, or a selective immune environment, mediated by matched donor/recipient HLA. We show that the pattern of reversion or fixation of HIV adaptations following transmission provides insight into the replicative cost, and likely compensatory networks, associated with specific adaptations in vivo. Furthermore, although transmitted viruses were commonly heavily pre-adapted to the child’s HLA genotype, we found evidence of de novo post-transmission adaptation, representing new epitopes targeted by the child’s T cell response. High-resolution analysis of HIV adaptation is relevant when considering vaccine and cure strategies for individuals exposed to adapted viruses via transmission or reactivated from reservoirs., Author summary Highly mutable pathogens utilise genetic variations within T cell epitopes as a mechanism of immune escape (viral adaptation). The diversity of the human leucocyte antigen (HLA) molecules that present viral targets to T cells in human populations partially protects against rapid population-level accumulation of human immunodeficiency virus (HIV) adaptations through horizontal transmissions. In contrast, vertical transmissions occur between haplo-identical mother/child pairs, and potentially include adaptive changes through father-mother-child transmission, representing a pathway to complete pre-adaptation to HLA alleles in child hosts over only two transmission events. We utilised next-generation sequencing to examine HIV evolution in the unique setting of vertical HIV transmission. We predict the in vivo replicative cost and immune benefit of specific HIV adaptations that could be used to inform vaccine design and cure strategies to combat viral immune adaptation.

Variation at HLA and KIR loci is associated with the severity of viral infections. To assess associations of genital HSV-2 infection with human HLA and KIR genetic loci, we measured the frequencies of genital herpes simplex virus (HSV) DNA detection and of genital lesions in HSV-2 seropositive persons. We followed 267 HSV-2 seropositive persons who collected daily genital swabs and recorded lesions for ⩾30 days. All persons were laboratory-documented as HIV-seronegative, and all were Caucasian by self-report. HSV detection rate and lesion frequency were compared by genotype using Poisson regression. Overall, HSV was detected on 19.1% of days and lesions on 11.6% of days. The presence of HLA-A*01 was directly associated with HSV detection frequency, whereas the presence of HLA-C*12 was inversely associated with HSV detection frequency. The presence of HLA-A*01 was directly associated with lesion rate, while HLA-A*26, -C*01 and -DQB1*0106 were associated with decreased lesions. We observed an interaction between the absence of both 2DS4del and HLA-Bw4 and higher lesion rate. Heterozygosity of HLA was also associated with reduced lesion frequency. Immune control of genital HSV infection relies on multiple interacting immunogenetic elements, including epistatic interactions between HLA and KIR.

Background Women comprise ~10% of people living with HIV in Australia, so are often underrepresented in research. Methods: This study invited clinicians providing care to women living with HIV to complete an anonymous survey containing questions related to four key areas: HIV (including diagnosis, treatment and virological outcomes), reproductive health (including sexual activity, contraception, pregnancy and outcomes) and linkage and retention in care. Results: In total, 484 surveys were received, with responses from all states and territories. Most women living with HIV in Australia are on treatment (>90%) and virologically suppressed (>90% have a viral load

Altres ajuts: This work was funded by grants from the National Institutes of Health (RO1AI46995 to P.G.) and the Wellcome Trust (WT104748MA to P.G.). This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research under contract no. HHSN261200800001E (to M.C.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), U01-AI35042 (Johns Hopkins University Bloomberg School of Public Health; Joseph Margolick, rincipal investigator [PI]), U01-AI35039 (Northwestern University; Steven Wolinsky, PI), U01-AI35040 (University of California, Los Angeles; Roger Detels and Oto Martinez, multiple principal investigators [MPI]), U01-AI35041 (University of Pittsburgh; Charles Rinaldo, PI), and UM1-AI35043 (Johns Hopkins University Bloomberg School of Public Health; Lisa Jacobson, PI). The SCOPE cohort was supported by the UCSF/Gladstone Institute of Virology and Immunology CFAR (P30 AI027763) and the CFAR Network of Integrated Systems (R24 AI067039). Additional support was provided by the Delaney AIDS Research Enterprise (DARE; AI096109 and A127966) and the amfAR Institute for HIV Cure Research (amfAR 109301). P.B. is a Jenner Investigator. I.W. and P.P. are funded by MRC Programme grant MR/K012037. The well-characterized association between HLA-B*27:05 and protection against HIV disease progression has been linked to immunodominant HLA-B*27:05-restricted CD8 + T-cell responses toward the conserved Gag KK10 (residues 263 to 272) and polymerase (Pol) KY9 (residues 901 to 909) epitopes. We studied the impact of the 3 amino acid differences between HLA-B*27:05 and the closely related HLA-B*27:02 on the HIV-specific CD8 + T-cell response hierarchy and on immune control of HIV. Genetic epidemiological data indicate that both HLA-B*27:02 and HLA-B*27:05 are associated with slower disease progression and lower viral loads. The effect of HLA-B*27:02 appeared to be consistently stronger than that of HLA-B*27:05. In contrast to HLA-B*27:05, the immunodominant HIV-specific HLA-B*27:02-restricted CD8 + T-cell response is to a Nef epitope (residues 142 to 150 [VW9]), with Pol KY9 subdominant and Gag KK10 further subdominant. This selection was driven by structural differences in the F pocket, mediated by a polymorphism between these two HLA alleles at position 81. Analysis of autologous virus sequences showed that in HLA-B*27:02-positive subjects, all three of these CD8 + T-cell responses impose selection pressure on the virus, whereas in HLA-B*27:05-positive subjects, there is no Nef VW9-mediated selection pressure. These studies demonstrate that HLA-B*27:02 mediates protection against HIV disease progression that is at least as strong as or stronger than that mediated by HLA-B*27:05. In combination with the protective Gag KK10 and Pol KY9 CD8 + T-cell responses that dominate HIV-specific CD8 + T-cell activity in HLA-B*27:05-positive subjects, a Nef VW9-specific response is additionally present and immunodominant in HLA-B*27:02-positive subjects, mediated through a polymorphism at residue 81 in the F pocket, that contributes to selection pressure against HIV. IMPORTANCE CD8 + T cells play a central role in successful control of HIV infection and have the potential also to mediate the eradication of viral reservoirs of infection. The principal means by which protective HLA class I molecules, such as HLA-B*27:05 and HLA-B*57:01, slow HIV disease progression is believed to be via the particular HIV-specific CD8 + T cell responses restricted by those alleles. We focus here on HLA-B*27:05, one of the best-characterized protective HLA molecules, and the closely related HLA-B*27:02, which differs by only 3 amino acids and which has not been well studied in relation to control of HIV infection. We show that HLA-B*27:02 is also protective against HIV disease progression, but the CD8 + T-cell immunodominance hierarchy of HLA-B*27:02 differs strikingly from that of HLA-B*27:05. These findings indicate that the immunodominant HLA-B*27:02-restricted Nef response adds to protection mediated by the Gag and Pol specificities that dominate anti-HIV CD8 + T-cell activity in HLA-B*27:05-positive subjects.

Prevention of cytomegalovirus (CMV) infection remains an important aspect of improving long term outcomes of solid organ transplantation and currently relies on prophylactic antiviral medication and early detection of viraemia or disease. Uptake of diagnostic tools to personalise assessment of CMV immunity and guide interpretation of viral testing remains low. We assessed the QuantiFERON-CMV assay in 54 Western Australian recipients of renal, heart, lung or liver allografts to determine the relationship between CMV-specific immunity, viraemia and disease following cessation of antiviral prophylaxis. We carried out an initial validation study which demonstrated that the QuantiFERON-CMV assay is highly precise and strongly correlated with CMV-specific antibodies in 30 healthy blood donors (sensitivity 82%, specificity 95%). In the solid organ transplant recipients we examined, the prevalence of asymptomatic CMV viraemia was high at 61% but only two patients ultimately developed CMV disease, both of whom had negative QuantiFERON-CMV responses, indicating lack of CMV T-cell immunity. The vast majority (94%) of patients who had spontaneous resolution or stability of asymptomatic CMV viraemia without any antiviral treatment had positive QuantiFERON-CMV responses. Positive QuantiFERON-CMV responses at cessation of antiviral prophylaxis were significantly associated with pre-transplant CMV seropositivity and the development of asymptomatic viraemia post-transplantation. Overall, 27% of patients were recommenced on antiviral therapy because of asymptomatic CMV viraemia. Patients with non-reactive QuantiFERON-CMV responses had earlier onset, higher level CMV viraemia compared to those with positive QuantiFERON-CMV responses, although the difference did not reach statistical significance. QuantiFERON-CMV results may contribute to decision making in concert with the serological risk profile, net state of immunosuppression and CMV viral load.

HIV circumvents HLA class I-restricted CD8 + T-cell responses through selection of escape mutations that leave characteristic mutational “footprints,” also known as HLA-associated polymorphisms (HAPs), on HIV sequences at the population level. While many HLA footprints are universal across HIV subtypes and human populations, others can be region specific as a result of the unique immunogenetic background of each host population. Using a published probabilistic phylogenetically informed model, we compared HAPs in HIV Gag and Pol (PR-RT) in 1,612 subtype B-infected, antiretroviral treatment-naive individuals from Mexico and 1,641 individuals from Canada/United States. A total of 252 HLA class I allele subtypes were represented, including 140 observed in both cohorts, 67 unique to Mexico, and 45 unique to Canada/United States. At the predefined statistical threshold of a q value of IMPORTANCE HLA footprints on HIV identify viral regions under intense and consistent pressure by HLA-restricted immune responses and the common mutational pathways that HIV uses to evade them. In particular, HLA footprints can identify novel immunogenic regions and/or epitopes targeted by understudied HLA alleles; moreover, comparative analyses across immunogenetically distinct populations can illuminate the extent to which HIV immunogenic regions and escape pathways are shared versus population-specific pathways, information which can in turn inform the design of universal or geographically tailored HIV vaccines. We compared HLA-associated footprints on HIV in two immunogenetically distinct North American populations, those of Mexico and Canada/United States. We identify both shared and population-specific pathways of HIV adaptation but also make the surprising observation that HLA footprints on HIV in Mexico overall are fewer and weaker than those in Canada/United States, raising the possibility that HLA-restricted antiviral immune responses in Mexico are weaker, and/or escape pathways somewhat less consistent, than those in other populations.

We hypothesized that HIV-specific CD8 T cell clonotypes can be stimulated by allogeneic HLA molecules. Multiple HIV-specific CD8 T cell clones were derived from 12 individuals with chronic HIV infection, specific for 13 different HIV Gag antigens and restricted to 7 different HLA molecules. The generated T cell clones were assayed for alloreactivity against a panel of single HLA class I expressing cell lines (SALs). HIV-specific T cells recognising at least one allogeneic HLA molecule could be identified from 7 of 12 patients tested. Allorecognition was associated with IFNγ cytokine production, CD137 upregulation and cytotoxicity, suggesting high avidity allo-stimulation. Allo-HLA recognition by HIV-specific T cells was specific to the HIV target peptide/HLA restriction and TCR TRBV usage of the T cells. HIV-specific T cells do crossreact against allogeneic HLA molecules in an epitope and TRBV specific manner. Therefore allo-HLA stimulation could be exploited to induce or augment HIV-specific T cell responses.

The extent to which HIV-1 clade B strains exhibit population-specific adaptations to host HLA alleles remains incompletely known, in part due to incomplete characterization of HLA-associated HIV-1 polymorphisms (HLA-APs) in different global populations. Moreover, it remains unknown to what extent the same HLA alleles may drive significantly different escape pathways across populations. As the Japanese population exhibits distinctive HLA class I allele distributions, comparative analysis of HLA-APs between HIV-1 clade B-infected Japanese and non-Asian cohorts could shed light on these questions. However, HLA-APs remain incompletely mapped in Japan. In a cohort of 430 treatment-naive Japanese with chronic HIV-1 clade B infection, we identified 284 HLA-APs in Gag, Pol, and Nef using phylogenetically corrected methods. The number of HLA-associated substitutions in Pol, notably those restricted by HLA-B*52:01, was weakly inversely correlated with the plasma viral load (pVL), suggesting that the transmission and persistence of B*52:01-driven Pol mutations could modulate the pVL. Differential selection of HLA-APs between HLA subtype members, including those differing only with respect to substitutions outside the peptide-binding groove, was observed, meriting further investigation as to their mechanisms of selection. Notably, two-thirds of HLA-APs identified in Japan had not been reported in previous studies of predominantly Caucasian cohorts and were attributable to HLA alleles unique to, or enriched in, Japan. We also identified 71 cases where the same HLA allele drove significantly different escape pathways in Japan versus predominantly Caucasian cohorts. Our results underscore the distinct global evolution of HIV-1 clade B as a result of host population-specific cellular immune pressures. IMPORTANCE Cytotoxic T lymphocyte (CTL) escape mutations in HIV-1 are broadly predictable based on the HLA class I alleles expressed by the host. Because HLA allele distributions differ among worldwide populations, the pattern and diversity of HLA-associated escape mutations are likely to be somewhat distinct to each race and region. HLA-associated polymorphisms (HLA-APs) in HIV-1 have previously been identified at the population level in European, North American, Australian, and African cohorts; however, large-scale analyses of HIV-1 clade B-specific HLA-APs in Asians are lacking. Differential intraclade HIV-1 adaptation to global populations can be investigated via comparative analyses of HLA-associated polymorphisms across ethnic groups, but such studies are rare. Here, we identify HLA-APs in a large Japanese HIV-1 clade B cohort using phylogenetically informed methods and observe that the majority of them had not been previously characterized in predominantly Caucasian populations. The results highlight HIV's unique adaptation to cellular immune pressures imposed by different global populations.