Translational medicine is a novel research branch that is quickly growing and bringing together distinct fields from the biomedical domain. The purpose of this research area is to discover new diagnostic methods and treatments, using the "bench-to-bedside” highly collaborative approach.

An important application of this new research principle is the involvement of genetics in the study of infectious diseases, particularly for HIV infection. Its importance marks in equal manner the personalized approach to therapy (precision medicine) as well as effective drug discovery and delivery processes.

In the past decade, a subset of patients with HIV infection have been described as elite controllers (ECs) and viremic controllers (VCs), both being part of the group of long-term non-progressors (LTNPs). These cohorts have elicited great clinical and research interest, as these individuals are capable of exhibiting a certain degree of immune control over viral replication. ECs and VCs exhibit undetectable or suppressed viral levels, respectively, for several years in the absence of antiretroviral (ARV) therapy, and this lack of progression has been described as being potentially associated with particular HLA genetic variants.

HLA alleles are also well known for the association between HLA-B*57:01 and the hypersensitivity reaction (HSR) to abacavir.

HLA alleles and HIV therapy

Abacavir (ABC), a nucleoside analog reverse transcriptase inhibitor (NRTI), has the potential of inducing a hypersensitivity reaction in roughly 5% of patients.¹Unless timely identified, HSR can be deadly.

Before initiating treatment with ABC, all patients are tested for the presence of the allele most often connected to the hypersensitivity reaction to ABC, HLA-B*57:01.²Patients who test positive will not be started on ABC treatment, and an alternate ARV agent will be included in the treatment regimen.

HSR can be identified based on at least two of the following clinical signs or symptoms: fever, rash, nausea, vomiting, cough, abdominal pain, dyspnea, fatigue and various gastrointestinal symptoms.

Certain studies report that about half of the cases of HSR to abacavir are related to the *57:01 variant, whereas other genetic factors, such as the genetic background of each individual, might contribute to the rest of the cases, as individuals testing negative for the HLA-B*57:01 variant may still be at 3% risk of HSR.^3,4,5

HLA alleles and susceptibility to HIV infection

HLA-A2 has been reported to be associated with reduced susceptibility against HIV infection, through several subtypes: HLA-A*02:01,HLA-A*02:05, HLA-A*02:14, HLA-A*68:01,HLA-A*68*02. HLA-A*11:01 and HLA-A*74:01have also been associated with a lower risk of HIV infection.^6,7,8Furthermore, another study has reported the association between HLA-A*74:01 and the good viremic control of HIV-1 infection.⁹

HLA-B genes have also been associated with a protective status,¹⁰ and among them, HLA-B*57:01 is the most widely reported to be associated with reduced susceptibility against HIV infection. One study has reported an association between viral suppression of HIV-1 in HLA-B*57:01+ elite controllers. Besides the HLA-B*57:01allele, different HLA-B alleles, such as HLA-B*51:01 and HLA-B*13:02 have also been associated with protection against HIV infection. Recently, higher CD4 cell counts and decreased level of viremia were noticed in carries of the HLA-B*57:01(+)/HLA-C-35C/C haplotype. ¹¹

A small number of HLA-Calleles have also been recognized as protective. Specifically, in 2013, HLA-C*06:02 and HLA-C*07:01 were individually described as conferring protection against HIV infection in a cohort of female sex workers.¹²

HLA-B*57:01

The HLA-B*57:01 gene is part of the major histocompatibility complex I, located on chromosome 6. This region codes for 3 groups of genes related to the immune system: HLA-A, HLA-B and HLA-C. The HLA-B protein can be found on the surface of the cellular membrane of almost all nucleated cells. The HLA-B molecule has a heterodimeric structure consisting of a strand coded by the geneHLA-B and the β2-microglobulin protein, encoded in chromosome 15. The α strand of the HLA-B protein is composed of 4 domains: cytoplasmic, transmembrane, one binding CD8+ cells and another forming the protein binding groove.

Usually the proteins interacting with the polymorphic region of the HLA-B protein are the result of normal cellular processes and are recognized as self-peptides. When a pathogenic agent infects a cell, its proteins are recognized by the T cell antigen receptors (TCR) as non-self-peptides, triggering the immune reaction and starting apoptotic processes.^13,14,15

The frequency of the HLA-B*57:01allele is variable as it can be found in multiple populations worldwide. Generally, among Caucasians, 5-10% of the individuals carry the allele, in African populations the allele is present in 1-2% of the people, while Indian populations have been reported to carry the HLA-B*57:01variant in almost 15% of the individuals. In the Eastern-European population, 1-3% of the individuals are carriers.^16,17

Apart from its involvement in the HSR to abacavir, the HLA-B*57:01 gene is also associated with flucloxacillin-induced hepatotoxicity. HLAalleles have been reported to be related to certain adverse events, but both genetic and epigenetic aspects have to be taken into account.

HIV elite and viremic controllers

HIV infected patients who display the ability to maintain normal CD4 cell counts in the absence of antiretroviral therapy have been described as long-term non-progressors (≥8 years)¹⁸ and particular subsets are represented by elite controllers and viremic controllers. The elite controllers can suppress viremia to undetectable level, less than 50 copies/mL while keeping their CD4 cell counts between 200 and 1000/µL in the absence of antiretroviral therapy.¹⁹Viremic controllers maintain HIV RNA levels between 50-2000 copies/mL without antiretroviral therapy.²⁰However, there is little information about the detailed underlying mechanism allowing the control of HIV infection, especially in elite and viremic controllers.

HIV-1 elite controllers can represent a potential functional model in the cure of HIV. This comes as a result of the hypothesis that this subset of individuals may be infected with a defective virus or that they possess an immune control mechanism working against the replication of competent virus. While defective virus has indeed been identified in the viral reservoirs of ECs,^21,22studies focused on transmission between chronic progressors (CPs) and elite controllers have shown that ECs transmit replication-competent virus, which is in turn associated with progressive disease in the new hosts.^23,10Furthermore, host factors play a significant role and they have to be taken into consideration as well. Elite controllers have shown epigenetic modifications at the 5’ long terminal repeat region, in particular, increased methylation with consequent limitation of active viral replication.^19,24

Rare HLA alleles such as HLA-B57*01, HLA-B27-*05 and HLA-C2seen in ECs play a protective role. However, the virus has been reported to evolve and develop HLA-escape variants, an evolutionary process that might be reversible with return to the original variant if transmitted to a new host. ^13,25

Precision medicine can benefit from individual and personalized treatment regimens, based on a combination of safe and effective antiretroviral drugs. Testing of all patients with HIV infection for the HLA-B*57:01 allele prior to commencing abacavir treatment, for example, brings undeniable benefits to the therapeutic process by significantly reducing the incidence of abacavir HSR.

Furthermore, the genetics underlying the susceptibility to acquiring HIV infection and the rate of virological or immunological progression or control in established HIV infection are complex and despite this field being intensely studied, further research is still needed to clarify how exactly this information can be put to practical use in the clinic.

1. Martin MA, Klein TE, Dong BJ, et al. Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and abacavir dosing. Clin Pharmacol Ther 2012;91:734-8. [Crossref]

2. Mattevi VS, Tagliari CFS. Pharmacogenetic considerations in the treatment of HIV. Pharmacogenomics 2017;:85-98. [Crossref]

3. Schnyder B, Adam J, Rauch A, Thurnheer MC, Pichler WJ. HLA-B*57:01⁺ abacavir-naive individuals have specific T cells but no patch test reactivity. J Allergy Clin Immunol 2013;132:756-8. [Crossref]

4. Martin MA, Hoffman JM, Freimuth RR, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and abacavir dosing: 2014 Update. Clin Pharmacol Ther 2014;95:499-500. [Crossref]

5. Martin MA, Klein TE, Dong BJ, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and abacavir dosing. Clin Pharmacol Ther 2012;91:734-8. [Crossref]

6. MacDonald KS, Fowke KR, Kimani J, et al. Influence of HLA supertypes on susceptibility and resistance to human immunodeficiency virus type 1 Infection. J Infect Dis 2002;181:1581-9. [Crossref]

7. Raghavan S, Selvaraj P, Swaminathan S, Narendran G. Short Communication: Association of HLA-A*1101 with resistance and B*4006 with susceptibility to HIV and HIV-TB: an in silico analysis of promiscuous T cell epitopes. AIDS Res Hum Retroviruses 2009;25:1023-8. [Crossref]

8. Koehler RN, Walsh AM, Saathoff E, et al. Class I HLA‐A*7401 is associated with protection from HIV‐1 acquisition and disease progression in Mbeya, Tanzania. J Infect Dis 2010;202:1562-6. [Crossref]

9. Sundaramurthi JC, Ashokkumar M, Swaminathan S, Hanna LE. HLA based selection of epitopes offers a potential window of opportunity for vaccine design against HIV. Vaccine 2017;35:5568-75. [Crossref]

10. May ME, Kwaa AK, Blankson JN. HIV-1 reservoirs in elite controllers: clues for developing a functional cure? Future Microbiol 2017;12:1019-22. [Crossref]

11. Leszczyszyn-Pynka M, Aksak-Was B, Urbańska A, Parczewski M. Protective effect of HLA-B∗5701 and HLA-C-35 genetic variants in HIV-positive Caucasians from Northern Poland. PLoS One 2015;10:e0127867. [Crossref]

12. Peterson TA, Kimani J, Wachihi C, et al. HLA class I associations with rates of HIV-1 seroconversion and disease progression in the Pumwani Sex Worker Cohort. Tissue Antigens 2013;81:93-107. [Crossref]

13. Rousseau CM, Lockhart DW, Listgarten J, et al. Rare HLA drive additional HIV evolution compared to more frequent alleles. AIDS Res Hum Retroviruses 2009;25:297-303. [Crossref]

14. Cummins NW, Badley AD. Mechanisms of HIV-associated lymphocyte apoptosis: 2010. Cell Death Dis 2010;1:e99. [Crossref]

15. Sevilya Z, Chorin E, Gal-Garber O, et al. Killing of latently HIV-infected CD4 T cells by autologous CD8 T cells is modulated by Nef. 2018;9:2068. [Crossref]

16. Stanojevic M, Alexiev I, Beshkov D, et al. HIV-1 molecular epidemiology in the Balkans - a melting pot for high genetic diversity. AIDS Rev 2012;14:28-36.

17. Martin MA, Kroetz DL. Abacavir pharmacogenetics - from initial reports to standard of care. Pharmacotherapy 2013;33:765-75. [Crossref]

18. Limou S, Zagury JF. Immunogenetics: Genome-wide association of non-progressive HIV and viral load control: HLAgenes and beyond. Front Immunol 2013;4:118. [Crossref]

19. Gonzalo-Gil E, Ikediobi U, Sutton RE. Mechanisms of virologic control and clinical characteristics of HIV+ elite/viremic controllers. Yale J Biol Med 2017;90:245-59.

20. Okulicz JF, Marconi VC, Landrum ML, et al. Clinical outcomes of elite controllers, viremic controllers, and long‐term nonprogressors in the US Department of Defense HIV natural history study. J Infect Dis 2009;200:1714-23. [Crossref]

21. Blankson JN, Bailey JR, Thayil S, et al. Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. J Virol 2007;81:2508-18. [Crossref]

22. Julg B, Pereyra F, Buzón MJ, et al. Infrequent recovery of HIV from but robust exogenous infection of activated CD4+ T cells in HIV elite controllers. Clin Infect Dis 2010;51:233-8. [Crossref]

23. Buckheit RW 3rd, Allen TG, Alme A, et al. Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs. Nat Commun 2012;3:716. [Crossref]

24. Palacios JA, Perez-Piñar T, Toro C, et al. Long-term nonprogressor and elite controller patients who control viremia have a higher percentage of methylation in their HIV-1 proviral promoters than aviremic patients receiving highly active antiretroviral therapy. J Virol 2012;86:13081-4. [Crossref]

25. Tjiam MC, Morshidi MA, Sariputra L, et al. Association of HIV-1 Gag-specific IgG antibodies with natural control of HIV-1 infection in individuals not carrying HLA-B57:01 is only observed in viremic controllers. J Acquir Immune Defic Syndr 2017;76:e90-2. [Crossref]