Here, we aimed to gain a better understanding of the immune response in an HIV/SARS-CoV-2 co-infected case compared to a SARS-CoV-2 mono-infected individual. Most PLWH who are on ART have an undetectable viral load and reconstituted CD4
+ T cell count. It is well documented that SARS-CoV-2 infection is associated with lymphopenia [
6]. Therefore, SARS-CoV-2 infection imposes a greater risk of lymphopenia in PLWH, in particular, in those who are ART naïve with a lower CD4
+ T cell count. This was evident in our co-infected case with low absolute whole blood lymphocyte count and < 1% CD4
+ T cell count in PBMCs. In the absence of ART, uncontrolled viral replication acts as the main driving force for CD4
+ T cell depletion and immune dysregulation [
12]. This was evidenced by the hyper-immune activation characterized by the expansion of CTLs expressing activation markers (CD38/HLA-DR) and co-stimulatory molecules in the co-infected case. This agrees with another study that has reported significantly higher proportion of activated (CD38/HLA-DR) CD4
+ and CD8
+ T cells in SARS-CoV-2 co-infected and HIV-unsuppressed compared with HIV suppressed individuals [
39]. Moreover, a negative correlation between the frequency of activated (CD38/HLA-DR) CD4
+/CD8
+ T cells with absolute CD4 counts was noted in co-infected individuals with unsuppressed HIV replication [
39]. Upregulation of co-inhibitory receptors (e.g. PD-1 and TIM-3) in T cells of COVID-19 patients has been documented [
6,
40]. Most of these reports speculated that T cells expressing co-inhibitory receptors are exhausted without conducting any functional studies [
3,
41]. Upregulation of co-inhibitory receptors does not necessarily mean an exhausted T cell phenotype [
42] as T cell exhaustion is characterized by functional impairment of T cell effector functions [
26]. Notably, transient expression of co-inhibitory receptors on activated T cells is meant to inhibit a robust and deleterious immune response in an acute setting [
43]. The massive production and release of inflammatory cytokines and cytolytic molecules (GzmB and perforin) in T cells expressing PD-1 and TIM-3 in the co-infected case compared to their counterparts lacking these co-inhibitory receptors resemble what occurs during T-cell activation [
44]. This agrees with our previous report that antigen-specific CD4
+ (CD154
+) and CD8
+ (CD137
+) T cells expressing co-inhibitory receptors had significantly higher levels of cytokine (e.g. TNF-α and IFN-γ) production compared to their negative siblings [
21]. A similar observation has been reported for antigen-specific PD-1
+CD4
+ T cells with greater IFN-γ producing capacity, which supports their activated phenotype [
20]. Of note, lower IFN-γ production by T cells in acute COVID-19 patients is widely reported [
3,
21,
45]. However, our co-infected case exhibited a robust IFN-γ response to both global and antigen-specific stimulation. These observations indicate that SARS-CoV-2 infection alters exhausted CTLs to an activated phenotype in PLWH. This implies that IFN-γ responses were not impaired in the co-infected case despite the anticipated T cell exhaustion due to untreated HIV infection [
8,
23,
27]. Therefore, hyper-T cell activation and a reduced proportion of MDSCs may exacerbate the immune response and contribute to cytokine storm commonly observed in COVID-19 patients [
5]. The hyperimmune activation is also accompanied by the expansion of non-classical monocytes in PLWH with inflammatory properties [
46]. Similarly, expansion of HLA-DR + monocytes supports their robust activation status [
5]. The striking observation was the disappearance of neutrophilia 2 days post ICU admission in the SARS-CoV-2 mono-infected case but a robust expansion of neutrophils (from 12.8 to 17.5 × 10
6/ml blood) in the co-infected case at the same time. It is reported that neutrophilia is more pronounced in COVID-19 patients with severe or critical disease [
47,
48]. In line with this, it was found that among COVID-19 patients’ non-survivors had a greater number of neutrophils than survivors [
48,
49]. It is worth mentioning that despite a high viral load and low CD4 count, our co-infected case did not exhibit signs of other infections at the time of admission to the ICU.
Of note, CECs are almost absent or in very low frequency in the peripheral blood of healthy individuals [
33,
50]. However, their massive expansion in the peripheral blood of acute COVID-19 patients infected with the SARS-CoV-2 (Wuhan strain) has been reported [
6,
34]. It is worth mentioning that those infected with the delta and omicron variants display lower frequency of CECs in their circulation [
35]. Similarly, a higher proportion of CECs in the peripheral blood of HIV-infected individuals, in particular, the ART-naïve subpopulation has been detected [
51]. However, SARS-CoV-2 variants differentially affect erythropoiesis and the Omicron variant is associated with the least expansion of CECs in the peripheral blood of COVID-19 patients [
35]. Therefore, a substantial expansion of CECs in the co-infected case versus mono-infected case highlights the synergistic effects of HIV and SARS-CoV-2 on erythropoiesis dysregulation. This was further demonstrated by the lower number of RBCs and anemia in the co-infected case.
However, there are a few study limitations that should be taken into consideration. This is a single case report, which is a major study limitation. Secondly the co-infected case was a female but the mono-infected case was a male. Hence, sex as a biological factor may influence the results [
55]. However, we have provided cumulative data to compare the range of values observed in a larger mono-infected cohort versus the co-infected case. Despite these limitations, we still believe our study provides an insight into the interplay between HIV and SARS-CoV-2. Therefore, the subpopulation of PLWH with insufficient immune reconstitution might be more vulnerable to SARS-CoV-2 infection, the development of COVID-19 disease and its associated complications as reported by others [
56]. The coexistence of both viruses in those with lower CD4
+ T cell count may evolve immune escape mutations leading to adverse public health outcomes. Additionally, unsuppressed HIV replication and hyper immune activation may lead to the depletion of CD4
+ T cells and subsequently diminished SARS-CoV-2 antigen-specific T cell response [
39]. As such, HIV-associated immune dysregulation in viremic individuals may negatively impact vaccine-induced cellular immunity. Therefore, integration of testing strategies or providing rapid SARS-CoV-2 tests to HIV-infected individuals in low-resource setting countries should be considered.