Does HIV disease progression differ by ancestry?

From Drs. Shuying (Sue) Li and Peter Gilbert, Vaccine and Infectious Disease Division

The human leukocyte antigen (HLA) molecules are proteins expressed on the cell membrane that can activate circulating immune cells, T cells specifically, for targeted cell killing. Alternatively, certain HLA proteins can reduce the broad cell killing mediated by natural killer (NK) cells in response to pathogens. HLA genes are highly polymorphic, meaning their coding sequences can vary substantially among healthy individuals. In fact, HLA genes have the greatest diversity of any genes within the human genome. In populations of African and European ancestry, some HLA variants (HLA-B*57 and HLA-B*27) have been associated with protection against HIV disease progression while others correlate with increased HIV load (or abundance) and disease progression. Individuals with Thai ancestry have a distinct subset of HLA genes as compared to neighboring Asian populations, as well as Africans and Europeans; thus, researchers believe that study of HLA genes in Thai populations may help explain why Thailand has one of the highest HIV prevalence rates in the Asia-Pacific region. Drs. Shuying (Sue) Li and Peter Gilbert at Fred Hutchinson Cancer Center in the Division of Vaccine and Infectious Disease, collaborated with researchers from both United States and international research institutes to investigate the association between HLA genotypes and HIV disease progression in the Thai population. This research was recently published in the journal of Cell, Host and Microbe.

“HIV infection is typically associated with an acute viral syndrome, followed by a prolonged generally asymptomatic period eventually leading to clinical AIDS,” state the researchers. “The kinetics of disease progression, in the absence of treatment, can vary between individuals from 1 year to more than 35 years for some rare individuals. Host [or person] genetic variations, specifically HLA alleles, have been shown to influence HIV disease progression and outcomes.” To investigate differences in HLA genes from people with Thai ancestry, the researchers analyzed data from three independent clinical trials that were sponsored by the US Military HIV research group (MHRP). These data sets included information about HIV status, treatment history for anti-HIV therapies, viral load (HIV abundance), and immune cell counts. To identify HLA gene variants associated with HIV disease progression, the researchers investigated correlations between HLA genes and viral load or AIDS symptom onset (time before CD4+ immune cell counts declined). The gene variant HLA-B*46 was found to correlate with high HIV abundance and quick decline in CD4+ immune cell counts, supporting increased disease progression (i.e., AIDS) for individuals with this HLA type. A high proportion of people in Thailand express the HLA-B*46 gene. While this HLA type was not associated with HIV infection susceptibility, the researcher’s findings suggest a role for HLA-B*46 in regulating a person’s susceptibility to HIV related disease.

The researchers analyzed HLA genotype data and identified that HLA-B*46 presence correlated with increased HIV disease progression. Single-cell RNA sequencing data revealed that HLA-B*46 likely inhibited NK cell-mediated killing of HIV infected cells to increase disease progression in these individuals.
The researchers analyzed HLA genotype data and identified that HLA-B*46 presence correlated with increased HIV disease progression. Single-cell RNA sequencing data revealed that HLA-B*46 likely inhibited NK cell-mediated killing of HIV infected cells to increase disease progression in these individuals. Figure taken from primary publication

To understand a potential mechanism of how HLA-B*46 increases HIV disease progression, the researchers analyzed single-cell RNA sequencing data for several cell types from HIV infected individuals with the HLA-B*46 gene or other HLA-B alleles. Previous studies in African and European cohorts had observed T cell activation by specific HLAs presenting HIV antigens to these cells that led to precise cell killing of HIV infected cells. These HLAs were also associated with better disease outcomes. For HLA-B*46, the absence or presence of this variant did not alter T cell activation. However, the NK cell population exhibited “active” transcriptional profiles in the absence of the HLA-B*46 allele and reduced “active” profiles in HLA-B*46 positive individuals. Upon further investigation, the researchers discovered that the HLA-B*46 protein interacts with proteins on NK cells to reduce NK cell mediated killing, thus interfering with a person’s ability to fight off HIV. These discoveries supported the preliminary findings that HLA-B*46 correlates with increased HIV disease progression.

“Remarkably, more than 25 years after the first description of specific HLA allele associations with HIV outcomes in multiple cohorts, we report that the presence of the HLA-B*46 allele likely impacts HIV outcomes among Asian populations,” commented the researchers. The Berlin patient highlights another example of ancestry impacting HIV infection. Individuals with Northern European ancestry have higher rates of a specific T cell receptor variant, CCR5 delta-32 allele. This natural variant in this population expresses a receptor on T cells that make these cells resistant to HIV infection. In the case of the Berlin patient, a stem cell transplant from the CCR5 delta-32 donor resulted in a cure from HIV for the Berlin patient. These published findings on HLAs and others like the Berlin patient are clear examples of how genetic ancestry is an important variable to consider. The high variation in human HLA alleles may result in significant differences in susceptibility to pathogen-related disease progression and call for specific therapeutic strategies. The researchers expand on this idea, stating that “understanding what contributed to [HLA] B*46 expansion in Asia and its effects in other diseases may be helpful in uncovering the role of NK cell functions in vivo [within a person].” The researchers are also interested in seeing how the HLA variants that are present in the Thai populations contribute to which HIV subtypes spread throughout Asia. These future studies will aid in understanding the fundamentals of HIV infection in Thailand and help to produce anti-viral therapies to help address the high rates of HIV prevalence in Thailand.

The spotlighted research was funded by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the DOD, the CDC/DHAP, and National Institute of Allergy and Infectious Disease.

Li SS, Hickey A, Shangguan S, Ehrenberg PK, Geretz A, Butler L, Kundu G, Apps R, Creegan M, Clifford RJ, Pinyakorn S, Eller LA, Luechai P, Gilbert PB, Holtz TH, Chitwarakorn A, Sacdalan C, Kroon E, Phanuphak N, de Souza M, Ananworanich J, O'Connell RJ, Robb ML, Michael NL, Vasan S, Thomas R. 2022. HLA-B∗46 associates with rapid HIV disease progression in Asian cohorts and prominent differences in NK cell phenotype. Cell Host Microbe. 30(8):1173-1185.e8.