Class I human leukocyte antigens (HLA) play an important role in the adaptive immune response by presenting antigens to CD8+ T cells. Studies have reported that several HLA class I alleles are associated with differential disease progression in human immunodeficiency virus (HIV)-infected individuals, however, few class I associations with resistance or susceptibility to HIV-1 infection have been reported. We typed HLA-A, -B and -C of >1000 women enrolled in the Pumwani Sex Worker Cohort using a sequence-based typing method. Kaplan-Meier analysis was used to identify alleles influencing seroconversion and disease progression to acquired immune deficiency syndrome (CD4 < 200/mm³). A*01 (P = 0.020), C*06:02 (P = 0.042) and C*07:01 (P = 0.050) are independently associated with protection from seroconversion. Women with any of these alleles are less likely to seroconvert [P = 0.00001, odds ratio (OR): 0.503, 95% confidence interval (CI): 0.320-0.790]. Conversely, A*23:01 (P = 0.004), B*07:02 (P = 0.003) and B*42:01 (P = 0.025) are independently associated with rapid seroconversion. Women with any of these alleles are twice as likely to seroconvert (P = 0.002, OR: 2.059, 95% CI: 1.290-3.285). The beneficial alleles confer threefold protection from seroconversion when compared with the susceptible alleles (P = 0.000001, OR: 0.268, 95% CI: 0.132-0.544). B*07:02 is the contributing allele, within the B7 supertype, to the rapid seroconversion. A*74:01 (P = 0.04/P = 0.006), B*14 (P = 0.003/P = 0.003) and B*57:03 (P = 0.012/P = 0.038) are independently associated with slower CD4+ decline and LTNP phenotype, while B*07:02 (P = 0.020), B*15:10 (P = 0.022) and B*53:01 (P = 0.007) are independently associated with rapid CD4+ T-cell decline. B7 supertype (P = 0.00006), B*35*-Py (P = 0.028) and B*35-Px (P = 0.001) were also significantly associated with rapid CD4+ T-cell decline. Understanding why these HLA class I alleles are associated with protection/susceptibility to HIV-1 acquisition and disease progression could contribute to the development of effective prophylactic and therapeutic vaccines for HIV-1.

Human immunodeficiency virus type 1 (HIV-1) is able to evade the host cytotoxic T-lymphocyte (CTL)response through a variety of escape avenues. Epitopes that are presented to CTLs are first processed in the presenting cell in several steps, including proteasomal cleavage, transport to the endoplasmic reticulum, binding by the HLA molecule, and finally presentation to the T-cell receptor. An understanding of the potential of the virus to escape CTL responses can aid in designing an effective vaccine. To investigate such a potential, we analyzed HIV-1 gag from 468 HIV-1-positive Kenyan women by using several bioinformatic approaches that allowed the identification of positively selected amino acids in the HIV-1 gag region and study of the effects that these mutations could have on the various stages of antigen processing. Correlations between positively selected residues and mean CD4 counts also allowed study of the effect of mutation on HIV disease progression. A number of mutations that could create or destroy proteasomal cleavage sites or reduce binding affinity of the transport antigen processing protein, effectively hindering epitope presentation, were identified. Many mutations correlated with the presence of specific HLA alleles and with lower or higher CD4 counts. For instance, the mutation V190I in subtype A1-infected individuals is associated with HLA-B*5802 (P ‫؍‬ 4.73 ؋ 10 ؊4 ), a rapid-progression allele according to other studies, and also to a decreased mean CD4 count (P ‫؍‬ 0.019). Thus, V190I is a possible HLA escape mutant. This method classifies many positively selected mutations across the entire gag region according to their potential for immune escape and their effect on disease progression.

Background: Precision medicine aims to link molecular targets in tumours with corresponding therapies, particularly for patients with rare cancers. Innovative approaches are needed to translate molecular opportunities into clinical care. The Cancer Molecular Screening and Therapeutics (MoST) program employs a molecular screening platform to identify molecular changes of therapeutic relevance (actionable changes) and a master protocol for multiple, parallel signal‐seeking clinical substudies, focused on therapies for patients with rare and neglected cancers. Methods and analysis: Archival pathology laboratory samples from patients with treatment‐refractory advanced solid cancer of any histologic type undergo molecular tumour profiling. Following review by a Molecular Tumour Board, eligible patients are offered treatment in therapeutic substudies. This novel master protocol allows expedited addition of individual substudies; at least 12 open label, single arm, signal‐seeking substudies during the initial 4 years of MoST are planned. The primary objectives are to identify signals of efficacy for developing biomarker‐driven therapies and biomarkers that more accurately predict response to therapy, as well as to evaluate the MoST design. Ethics approval: The program has been approved by the St Vincent's Hospital Sydney Human Research Ethics Committee (reference, HREC/16/SVH/23). Dissemination of results: A report summarising and interpreting collected study data will be published. Our findings will be presented at national and international conferences and scientific meetings, and published in peer‐reviewed journals. Trial registration: Australia New Zealand Clinical Trials Registry: ACTRN12616000908437 (8 July 2016).