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. 2025 Jul 14;52(5):249–255. doi: 10.1111/iji.70003

Co‐Occurrence of HIV‐Susceptibility and ‐Protective HLA Alleles Is a Possible Contributor to the Development of Primary HIV‐Associated Thrombocytopenia (PHAT): A Cross‐Sectional Study

Walter J Janse van Rensburg 1,✉, Anne‐Cecilia van Marle 2,3, Lomari Geertsema 1
PMCID: PMC12418909  PMID: 40660618

ABSTRACT

Primary HIV‐associated thrombocytopenia (PHAT) is an isolated thrombocytopenia in HIV‐positive individuals in the absence of secondary causes. The presence of certain Human Leukocyte Antigens (HLA) has been linked to individuals’ immune response to HIV and the development of immune‐mediated thrombocytopenic disorders. Considering the established associations between HLA and HIV infection and HLA and immune‐mediated thrombocytopenias, we hypothesise that specific HLA alleles may also increase the risk of developing PHAT, a condition that links both HIV and immune‐mediated thrombocytopenia. Therefore, the study aimed to determine the frequency of high‐resolution HLA alleles in patients presenting with possible PHAT. Following a detailed screening process, we evaluated the HLA profiles of 43 participants with probable PHAT using the Axiom Precision Medicine Diversity Array (PMDA) Kit on the GeneTitan Multi‐Channel instrument. No single HLA allele was found to be more prominent in our PHAT population. However, 93.02% of participants had both HIV‐protective and HIV‐susceptible alleles. The potential mechanism causing thrombocytopenia to be the only clinically relevant haematological abnormality in these patients remains to be explored. We concluded that the presence of both an HIV‐protective and HIV‐susceptibility allele in the same individual may cause antagonistic immune reactions, resulting in thrombocytopenia in HIV‐positive individuals. We propose future long‐term follow‐up studies to determine the progression and outcome in patients with PHAT.

Keywords: HIV, PHAT, Primary HIV‐associated thrombocytopenia

1. Introduction

Primary HIV‐associated thrombocytopenia (PHAT) is thrombocytopenia in HIV‐positive individuals in the absence of secondary causes. (O'Bryan et al. 2015) The pathophysiology involves suppressed or ineffective platelet production, increased consumption, immune‐mediated destruction, and splenic sequestration. (Scaradavou 2002) Taking into account that South Africa has the highest prevalence of HIV globally, the frequency of PHAT is suspected to be significant. (Stats SA 2022) Our group previously reported that one in every six HIV‐positive patients with isolated thrombocytopenia has PHAT. However, this likely underestimates the prevalence of PHAT, considering that patients with comorbidities and additional cytopenias were excluded from the study. (Geertsema et al. 2022) Still, the relatively high prevalence of PHAT requires further exploration into the possible contributing aetiological factors.

Human leukocyte antigen (HLA) is an essential component of an individual's immune response. HLA plays an interrelated role in the intrathymic differentiation of immature T‐cells, thereby contributing to the final set of T‐cells in circulation and the activation of mature T‐cells through selective antigen presentation. (Coico and Sunshine 2015) An association between HLA genotypes and specific diseases has been investigated since the 1960s. (Howell 2014; Janse van Rensburg et al. 2021) The immunopathogenesis of multiple diseases has since been linked to the presence or absence of certain HLA alleles (Blackwell et al. 2009), including susceptibility to and progression of patients with HIV (Howell 2014; Gregersen 2011; Mellet et al. 2019). Determining HLA disease association provides insight into the disease pathogenesis and can facilitate the development of new therapeutic targets. (Simmonds and Gough 2007)

Numerous HIV‐HLA allele associations have been identified, denoting that HIV‐associated disorders may also have HLA allele associations. (International HIV Controllers Study 2010) Rapid progression to AIDS has been linked to class‐I HLA‐B*35 and HLA‐C*04 within populations of European descent. Amino acids coded by HLA‐B*35, namely B*35:02 and B*35:03, confer a higher risk for AIDS progression, while HLA‐B*35:01 presents a lower risk (Gregersen 2011; Carrington et al. 1999). HLA‐B*27 and HLA‐B*58 are considered protective against HIV progression (Blackwell et al. 2009; Gregersen 2011; Ghodke et al. 2005), whilst HLA‐DRB1*01 is associated with decreased disease progression in East African populations (MacDonald et al. 2000). A study in a Turkish population found that HLA‐B*15:01, *35:01, *35:08 and *51:01 promote HIV susceptibility, whilst HLA‐B*07:02, *14:01, *44:01 and *55:01 are likely protective (Darbas et al. 2022). Two independent African studies found HLA‐A*02:05 protective against HIV (MacDonald et al. 2000; Koehler et al. 2010).

HLA alleles associated with increased HIV susceptibility described within the South African population include HLA‐B*08/08:01, HLA‐B*18/18:01, HLA‐B*45/45:01, HLA‐B*51:01, and HLA‐B*58:02. (Mellet et al. 2019) Additionally, HIV‐protective HLA alleles identified within the South African population, include HLA‐A*74/74:01, HLA‐B*13:02, HLA‐B*44:03, HLA‐B*57:03, HLA‐B*58:01 and HLA‐B*81:01. HLA‐HIV association studies in the South African population, where the global prevalence of HIV is the highest, have become a vital source of information contributing to our understanding of the disease pathogenesis (Mellet et al. 2019; Tshabalala et al. 2015).

Haematological abnormalities are commonly present in HIV‐infected individuals (Firnhaber et al. 2010). The underlying pathophysiological mechanisms are multifactorial and include impaired haematopoiesis, immune‐mediated cytopenias, and coagulopathies (Izak and Bussel 2014; Vishnu and Aboulafia 2015; Kumar et al. 2016). Thrombocytopenia is one of the major manifestations of AIDS, in addition to frequently being a primary manifestation of HIV (Scaradavou 2002; Vannappagari et al. 2011).

HLA has also been associated with haematological disorders. Immune thrombocytopenia (ITP) and thrombotic thrombocytopenic purpura (TTP) are two thrombocytopenic disorders with known HLA associations, indicating a possible link between the HLA genotype and the thrombocytopenic phenotype (Figure 1). A higher incidence of ITP is reported amongst individuals with HLA‐Bw*38 and HLA‐A*28 alleles, which correlate with acute and chronic ITP, respectively. Additionally, antiplatelet antibodies are also more frequently detected in individuals with HLA‐DRB1*04:05, suggesting an association of these HLA alleles with a higher risk of the development of ITP (Asnafi et al. 2019). HLA‐DQB1*02:02, HLA‐DRB1*11 (John et al. 2012) and HLA‐DRB1*15 (Asnafi et al. 2019) alleles are more frequently encountered in adult patients with idiopathic TTP, and HLA‐DQB1*03:01 has also been implicated as a risk factor in patients presenting with autoimmune TTP (Joly et al. 2020), whilst HLA‐DRB1*04 (Scully et al. 2010), HLA‐DR53 (Joseph et al. 1994), HLA‐DQB1*02, HLA‐DRB1*07 and HLA‐DRB1*13 (Asnafi et al. 2019) appear to play a protective role with decreased susceptibility to acquired TTP. Interestingly, HLA‐DQB1*06 has been implicated in both protective and high‐risk haplotypes (Sinkovits et al. 2017).

FIGURE 1.

FIGURE 1

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Overlapping disorders of HIV, immune‐mediated thrombocytopenia, thrombotic thrombocytopenic purpura and their HLA associations. (Blackwell et al. 2009; Gregersen 2011; Mellet et al. 2019; Carrington et al. 1999; Ghodke et al. 2005; MacDonald et al. 2000; Darbas et al. 2022; Koehler et al. 2010; Peterson et al. 2013; Kløverpris et al. 2012; Asnafi et al. 2019; John et al. 2012; Joly et al. 2020; Scully et al. 2010; Joseph et al. 1994; Sinkovits et al. 2017).

Considering the established associations between HLA and HIV infection as well as immune‐mediated thrombocytopenias such as ITP and TTP (Mellet et al. 2019; Asnafi et al. 2019) and the association between HIV‐induced immune dysregulation and thrombocytopenia (Scaradavou 2002; Perkocha and Rodgers 1988; Saif and Greenberg 2001; Passos et al. 2010), we hypothesised that specific HLA alleles may also increase the risk of developing PHAT, a condition that links both HIV and immune‐mediated thrombocytopenia (Figure 1).

Thus, the aim of our study was to characterise the HLA genotypes in patients presenting with PHAT in a central South African population.

2. Methodology

Approval to conduct this study was obtained from the Health Sciences Research Ethics Committee (HSREC) in the Faculty of Health Sciences at the University of the Free State (UFS‐HSD2020/1752/2302), as well as from the National Health Research Database (NHRD) of the Free State and Northern Cape Departments of Health.

2.1. Sample Selection

The target population was identified by implementing a screening method of all available medical information to select those who comply with the inclusion criteria, that is, the presence of isolated thrombocytopenia on the full blood count (platelet count below 150 × 109 /L) in HIV‐positive individuals above the age of 18 years, of either sex, with no additional comorbidities. The available medical information included laboratory test results obtained from the NHLS TrakCare database and clinical notes from patient hospital records. A total of 6068 patient files were screened from the beginning of February 2021 until the end of April 2022. The screened files included those from patients seen at the National District Hospital, Pelonomi Regional Hospital, and Universitas Academic Hospital in Bloemfontein, as well as Robert Mangaliso Sobukwe Hospital in Kimberley, in South Africa. Ultimately, we identified 43 patients with probable PHAT (Geertsema et al. 2022).

DNA was extracted from whole blood using the Quick‐DNA Miniprep Kit (Zymo Research, USA) according to the manufacturer's instructions. High‐resolution HLA typing of each participant was performed using the Axiom Precision Medicine Diversity Array (PMDA) Kit's 96‐Array Format Manual Workflow (ThermoFisher, USA) on the GeneTitan Multi‐Channel (MC) instrument (ThermoFisher, USA). The HLA type was determined using GeneTitan MC Protocol for Axiom HLA Analysis software (ThermoFisher, USA), and the allele frequency was calculated using Microsoft Excel spreadsheets.

3. Results

3.1. Clinical Data

Approximately 85.4% (n = 35/43) of PHAT participants were indicated to be immunocompromised (CD4+ < 500 cells/µL), of which 68.6% were severely immunocompromised (CD4+ < 200 cells/µL). A total of 72.1% of the total PHAT population (n = 31/43) were on antiretroviral therapy (ART), with 18.6% (n = 8/43) not on ART, and in 9.3% (n = 4/43) the ART status was unknown.

3.2. HLA Data

The high‐resolution HLA type for eleven loci (HLA‐A, HLA‐B, HLA‐C, HLA‐DPB1, HLA‐DQB1, HLA‐DRB1, HLA‐DPA1, HLA‐DQA1, HLA‐DRB3, HLA‐DRB4, and HLA‐DRB5) of all 43 probable PHAT participants was successfully determined. For conciseness, we only describe the three most frequent alleles found for each HLA group (Table 1).

TABLE 1.

Most frequent HLA alleles within our PHAT population.

High‐resolution HLA class I High‐resolution HLA class II
HLA‐A HLA‐B HLA‐C HLA‐DPB1 HLA‐DQB1 HLA‐DRB1
30:02 (12.8%) a 58:02 (15.1%) b 07:01 (16.3%) a 01:01 (36.0%) 06:02 (18.6%) c 03:02 (14.0%)
30:01 (10.5%) 42:01 (11.6%) a , b 06:02 (16.3%) a 04:02 (16.3%) 05:01 (15.1%) 11:01 (12.8%) c
02:05 (10.5%) a 44:03 (9.3%) a 17:01 (15.1%) 18:01 (11.6%) 04:02 (14.0%) 13:01 (8.1%)
29:02 (10.5%) 07:01 (8.1%)
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a

Indicates an HIV‐protective allele.

b

Indicates an HIV‐susceptibility allele.

c

Indicates a TTP‐susceptibility allele.

In our study, the most prevalent MHC class‐I HLA‐A alleles were HLA‐A*30:02 (12.8%), HLA‐A*30:01 (10.5%), HLA‐A*02:05 (10.5%), and HLA‐A*29:02 (10.5%) (due to the last three alleles having the same allele frequency, we included all three).

The most common HLA‐B and HLA‐C alleles in our PHAT population were HLA‐B*58:02 (15.1%), HLA‐B*42:01 (11.6%), HLA‐B*44:03 (9.3%), and HLA‐C*07:01 and HLA‐C*06:02, with equal allele frequencies (16.3%), in addition to HLA‐C*17:01 (9.3%), respectively.

We obtained high‐resolution HLA typing with four‐digit resolution for eight MHC class‐II genes and further discussed the most common class‐II genes: HLA‐DPB1, HLA‐DQB1 and HLA‐DRB1.

HLA‐DPB1*01:01 (36.0%), HLA‐DPB1*04:02 (16.3%), and HLA‐DPB1*18:01 (11.6%) were the most prevalent alleles at the HLA‐DPB1 locus in our PHAT population.

Of the HLA‐DQB1 alleles reported, HLA‐DQB1*06:02 (18.6%), HLA‐DQB1*05:01 (15.1%), and HLA‐DQB1‐04:02 (14.0%) were the most prevalent alleles in our study.

HLA‐DRB1 was the most diverse MHC Class II allele, with the highest number of alleles in our PHAT population. HLA‐DRB1*03:02 (14.0%), HLA‐DRB1*11:01 (12.8%), HLA‐DRB1*13:01 (8.1%) and HLA‐DRB1*07:01 (8.1%) were the most frequent alleles at this locus.

A wide variety of both HIV‐protective and HIV‐susceptibility alleles were found in our PHAT population. However, none of the alleles had a frequency that was remarkably different than what has been previously found by previous studies in the South African population (Table 2).

TABLE 2.

Frequency of HIV‐associated HLA alleles within our PHAT population. The underlined alleles have contradicting roles in HIV‐susceptibility.

HIV‐Protective HLA Alleles HIV‐Susceptible HLA Alleles
HLA‐A HLA‐B HLA‐C HLA‐DRB1 HLA‐A HLA‐B HLA‐C HLA‐DRB1
01:01 (3.5%) 07:02 (5.8%) 06:02 (16.3%) 01 (4.7%) 23:01 (5.8%) 07:02 (5.8%) 04 (14.0%) No alleles detected
02:05 (10.5%) 13:02 (2.3%) 07:01 (16.3%) 68:02 (8.1%) 15:01 (2.3%) 07:02 (5.8%)
30:02 (12.8%) 27 (2.3%) 08/08:01 (7%)
74/74:01 (4.7%) 35:01 (1.2%) 18/18:01 (3.5%)
42:01 (12.8%) 42:01 (12.8%)
44:03 (9.3%) 45/45:01 (5.8%)
57:03 (2.3%) 58:02 (15.1%)
58:01 (5.8%)
81:01 (4.7%)
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4. Discussion

HLA is a known contributing factor to disease aetiology and predisposition but has not yet been investigated in the setting of PHAT. We set out to characterise the HLA genotypes in a PHAT population of central South Africa. Similar to other studies conducted in South African populations, the MHC class‐I HLA‐A*30 was found to be one of the most common allele groups (Janse van Rensburg et al. 2021; Tshabalala et al. 2015; De Kock et al. 1997; Loubser et al. 2020). Additionally, multiple studies have reported HLA‐B*58:02, found in 15.1% of our study cohort, to be one of the most common HLA‐B alleles within the African population (Janse van Rensburg et al. 2021; Tshabalala et al. 2015; Loubser et al. 2020). Low‐resolution HLA‐C*06 and HLA‐C*07 have previously been shown to be common allele groups in the central South African population (Janse van Rensburg et al. 2021; De Kock et al. 1997). Similarly, two other South African studies reported a high frequency of high‐resolution HLA‐C*06:02 and HLA‐C*07:01 (Loubser et al. 2020; Tshabalala et al. 2018), emphasising the prevalence of these HLA‐C alleles amongst South Africans, albeit not unique to the central South African population. Notably, HLA‐C*07:01 and HLA‐C*06:02 were present in 58.1% (25/43) of our PHAT participants.

Except for HLA‐DPB1 alleles, the most common MHC class II genes detected in our study cohort seemed to reflect the allele frequencies determined in other South African studies (Tshabalala et al. 2015; Loubser et al. 2020; Tshabalala et al. 2018; Tshabalala et al. 2022). Loubser et al. (2020) determined a similar HLA‐DQB1*06:02 allele frequency of 19.4% in their healthy African population, whilst Tshabalala et al. (2015) and (2022) suggested a higher frequency of HLA‐DQB1*06:02 in a disease‐burdened population. Except for HLA‐DRB1*03, which has only been reported in one other South African study (Janse van Rensburg et al. 2021), the other frequent HLA‐DRB1 alleles found in this study (*11:01, *13:01, and *07:01) have all been confirmed to be prevalent among South Africans (Janse van Rensburg et al. 2021; Tshabalala et al. 2015; Loubser et al. 2020; Tshabalala et al. 2018; Tshabalala et al. 2022). According to the IMGT/HLA database, HLA‐DRB1*03:02 is primarily reported in individuals of African descent (Robinson et al. 2020).

The preliminary assessment of our results indicated no particularly conspicuous allele association with PHAT, as all of the most frequent alleles within our PHAT population have previously been described in unrelated studies conducted in similar geographical locations (Janse van Rensburg et al. 2021; Tshabalala et al. 2015; De Kock et al. 1997; Loubser et al. 2020; Tshabalala et al. 2018; Tshabalala et al. 2022). Interestingly, however, further analysis showed that the majority of PHAT patients contained alleles associated with either HIV protection, HIV susceptibility, and disease progression, or both. The most prevalent HLA Class‐I alleles detected in our PHAT population have all been previously described in African populations to affect HIV susceptibility. HLA‐A*30:02 (12.8%), HLA‐C*07:01 (16.3%), and HLA‐C*06:02 (16.3%) alleles confer a protective mechanism (Koehler et al. 2010; Peterson et al. 2013), whilst HLA‐B*58:02 (15.1%) is associated with increased susceptibility to HIV infection (Mellet et al. 2019). HLA‐B*58:01 and HLA‐B*58:02 have also been linked with HIV disease progression (Janse van Rensburg et al. 2021; Mellet et al. 2019). Considering the selection bias of only including HIV‐positive individuals in our study cohort, the high prevalence of these alleles was anticipated and further supports their designation as HIV‐susceptible alleles. However, the high prevalence of HIV‐protective alleles within our HIV‐positive population was unexpected. Unfortunately, definite conclusions regarding the effects of these HIV‐associated alleles on the disease course of a patient could not be made, as we did not monitor the progression of their disease. HLA‐B*35, globally the most common allele and known to be associated with HIV susceptibility and increased disease progression (Mellet et al. 2019), was not detected in our PHAT population (frequency of 0%).

Interestingly, all 43 participants with probable PHAT (n = 43/43; 100%) had at least one HIV‐associated HLA Class‐I allele (either protective or susceptible). HIV‐protective HLA class‐I alleles were present in 41 of the 43 study participants, whilst one participant had the HLA Class‐II allele, DRB1*01:02, which in its low‐resolution form (DRB1*01) has been described as HIV‐protective (MacDonald et al. 2000).

Only two (n = 2/43) participants did not have an HIV‐susceptible HLA class‐I allele. However, both these participants had HLA Class II alleles linked to TTP‐susceptibility, namely HLA‐DQB1*03:01 and HLA‐DRB1*11:02. In fact, 74.42% (n = 32/43) of participants had TTP‐susceptibility alleles. Considering that participants would have been excluded if an additional cytopenia (e.g., anaemia) were present, it's unlikely that these participants had TTP. Although beyond the scope of this research, it would have been interesting to know if they previously had or subsequently developed TTP. Additionally, 30.2% (n = 13/43) of participants had HLA alleles linked to ITP susceptibility, namely HLA‐B*08 (7%), HLA‐DRB1*04:01 (7%), HLA‐DRB1*04:05 (1.2%) and HLA‐DQB1*06:01 (2.3%). None of these alleles were among the top three most common alleles in their groups, as shown in Table 1.

The most noteworthy finding of our study was that when evaluating both the HIV‐protective (n = 42/43; 97.67%) and susceptibility alleles (n = 41/43; 95.35%), 40 of our participants (n = 40/43; 93.02%) had both HIV‐protective and HIV‐susceptibility alleles present. Due to the study size and lack of outliers in the clinical data, we cannot make any conclusive inferences regarding participants with co‐occurring contrasting HIV‐associated alleles in our PHAT population.

We can, however, propose a hypothesis. Considering that only HIV‐positive individuals with isolated thrombocytopenia and no additional comorbidities were included in our study, this selection would favour patients with an otherwise indolent disease course or possibly adequate disease control. Thus, we can postulate that the two alleles with opposing HIV disease progression mechanisms may interact, having a largely equalising effect. This phenomenon has been previously described in a South African population, where it was found that patients possessing both protective and susceptible HIV‐associated HLA alleles showed no significant difference in disease progression compared to patients who had neither. This suggests that the coexpression of protective and susceptible HLA alleles has a potentially neutralising additive effect (Leslie et al. 2010), possibly through epistatic gene‐gene interaction. However, this neutralising effect on HIV disease progression does not necessarily negate the individual's immune response to the viral peptides presented by opposing HIV‐associated HLA alleles. Rather, it may contribute to immune‐mediated thrombocytopenia through molecular mimicry of HIV peptides (Li et al. 2005). Whether an immune‐mediated mechanism for the underlying thrombocytopenia as the only clinically relevant biological abnormality is linked to the opposing effects of the HLA alleles remains to be determined. We believe that this finding warrants additional exploration.

Another possible cause of thrombocytopenia in HIV‐positive individuals is the ART used to suppress their HIV infection (Tan et al. 2023). In South Africa, the preferred first‐line ART regimen is a combination of tenofovir, lamivudine and dolutegravir (TLD) (National Department of Health 2023). All three of these agents have, on rare occasions, been associated with thrombocytopenia (Nakaharai et al. 2017; Jain et al. 2017; Taylor et al. 2024). However, with nearly a fifth of our PHAT population not on ART, the influence of ART on the development of PHAT could not be confirmed in our study population.

5. Conclusion

In conclusion, we found the most prevalent HLA alleles within our PHAT study population to align with the most common alleles previously described within the South African population. However, the high prevalence of HIV‐protective alleles, as well as the co‐expression of both HIV‐susceptible and protective alleles in this patient cohort, were intriguing findings that warrant further exploration.

5.1. Limitations and Future Studies

Due to the small study population size (n = 43), we could not make statistical inferences regarding our results. Additionally, due to the study design being a cross‐sectional study, we were unable to conclude on multiple findings that require the assessment of the clinical disease course. Thus, the impact of ART initiation and longitudinal exposure on the platelet count and the implication of co‐occurring HIV‐susceptive and HIV‐protective alleles in HIV‐positive participants need further investigation in a disease progression‐based study. However, as the first study to investigate PHAT in our central South African population, we believe our study identified noteworthy findings that warrant further investigation into this rare disorder.

Author Statement

All authors have read and approved the final version of the manuscript. Walter Janse van Rensburg had full access to all the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

Ethics Statement

Approval to conduct this study was obtained from the Health Sciences Research Ethics Committee (HSREC) in the Faculty of Health Sciences at the University of the Free State (UFS‐HSD2020/1752/2302), as well as from the National Health Research Database (NHRD) of the Free State and Northern Cape Departments of Health.

Consent

Informed consent and genetic informed consent were obtained in the patients’ language of choice for all in‐hospital patients. Informed consent and genetic informed consent forms were approved by the HSREC of the UFS. Consent forms were made available in either English, Afrikaans, Sotho, or Setswana.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

Walter Janse van Rensburg affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Acknowledgement

The authors have nothing to report.

van Rensburg, W. J J. , Marle A.‐C. van, and Geertsema L.. 2025. “Co‐Occurrence of HIV‐Susceptibility and ‐Protective HLA Alleles Is a Possible Contributor to the Development of Primary HIV‐Associated Thrombocytopenia (PHAT): A Cross‐Sectional Study.” International Journal of Immunogenetics 52, no. 5: 52, 249–255. 10.1111/iji.70003

Funding: The study was partly funded by an NHLS Research Trust Development Grant (Grant number PR2110607). The funder had no influence over the study design; collection, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.

Data Availability Statement

Datasets are available from the corresponding author at reasonable request.

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