Neutropenia and myelosuppression are commonly observed in PLWHA. In this study, we identified 263 patients with neutropenia, which constituted 33.7% of the overall cohort examined. We identified decreased bone marrow granulocyte ratio, decreased peripheral blood mononuclear cell count, decreased B-lymphocyte count and decreased CRP as risk factors associated with the development of neutropenia. Additionally, an ANC count of ≤ 0.5 × 10^9/L was linked to a poorer prognosis in individuals living with HIV/AIDS (PLWHA).

We concluded that decreased bone marrow granulocyte ratio represented as independent risk factor for neutropenia in PLWHA. Because of the relative short lifespan of neutrophils in the systemic circulation, maintaining normal levels of neutrophils in the peripheral blood is largely dependent on the hematopoietic tissues producing sufficient numbers of neutrophils on a daily basis. Previous studies have shown that HIV infection can impair the function of hematopoietic stem/progenitor cells (HSPCs) [13, 14]. In vitro investigations have revealed that HIV is cytotoxic to infected HSPCs, resulting in the death of these hematopoietic precursors [15]. Apart from this, HIV is also capable of infecting a variety of cell types in the bone marrow hematopoietic niche, leading to an increase in macrophage-like cells and a decrease in the number of fibroblastic population [16]. HIV infection of various bone marrow stromal niche cell types may mediate myelosuppression and impair granulopoiesis by disrupting cellular interactions between niche cells and hematopoietic cells. This disruption weakens the supportive role of niche structures for hematopoietic cells and alters the production of cytokines and hematopoietic growth factors by niche cells, thereby compromising the humoral regulation of myeloid/granulocytic lineage development within the bone marrow [16,17,18].

Decreased peripheral blood mononuclear cell count was a risk factor for neutropenia. Neutrophils and monocytes are derived from a common progenitor, granulocyte-macrophage (GM) progenitors, which implies a possible quantitative correlation between monocytes and neutrophils [19]. Monocytes and macrophages serve as essential components of the innate immune system. And they also play pivotal roles in the initiation of adaptive immunity. Monocytes enter the peripheral circulation after developmental differentiation in the bone marrow from stem cells of the granulo-monocytic lineage. Studies have shown that both monocytes and macrophages can be infected by HIV-1 and may serve as viral reservoirs [20,21,22]. Following HIV infection, there is a progressive decline in the production of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) by blood monocytes. Notably, this reduction in GM-CSF production exhibits a significant correlation with the viral load present in the peripheral blood mononuclear cells of the patient [23, 24]. HIV may have a substantial impact on the onset of neutropenia by direct invasion of stem cells of the granulo-monocytic lineage or by influencing the reduction of GM-CSF production.

In addition, decreased CD19+B-Lymphocytes was also a risk factor for neutropenia. B-Lymphocytes, responsible for the secretion of antibodies, have a substantial impact on mediating the humoral immune response to viral and bacterial infections by neutralizing, conditioning, mediating cell death through antibodies, and activating complement pathways. Additionally, CD19+B-lymphocytes play a crucial role in regulating the immune system through antigen presentation and cytokine secretion. Researches have demonstrated that prolonged HIV-1 infection leads to a reduction in peripheral blood B-cell count and modifications in subpopulation proportions. Furthermore, it causes impairments in B-cell function, resulting in reduced antigen-specific antibody-secreting and cytokine-secreting capabilities as well as a decline in its specific immune response function [25, 26].

C-reactive protein is a non-specific biomarker of acute phase inflammation, which is elicited by interleukin (IL)-1 and IL-6. Studies have shown that C-reactive protein concentrations increase with infection and are independent of HIV status [27, 28]. What is clear is that neutropenia leads to a greatly increased risk of opportunistic infections. Interestingly, lower concentrations of CRP were associated with neutropenia in our findings. In PLWHA, infection with tuberculosis led to high levels of CRP, whereas the increase in CRP concentration in patients infected with Talaromyces marneffei and Pneumocystis pneumonia was significantly lower than that in patients infected with common bacterial pathogens [27, 29,30,31]. In this study, patients in the neutropenia group were more likely to be infected with TM (p < 0.001), PCP (p < 0.001) compared with the non-neutropenia group while there was no significant difference in the proportion of TB infections between the two groups. This may be one of the reasons why CRP was lower in the neutropenia group, and another reason may be that monocytes are lower in the neutropenia group, and IL-1 and IL-6 secreted by monocytes and macrophages promotes CRP synthesis [32, 33].

In summary, we believe that there are at least three causes for neutropenia during HIV infection. First, the cytotoxic effect of HIV on HSPCs results in a reduction in neutrophil production. Second, HIV disrupts the hematopoietic growth factor and cytokine environment within the niche network, leading to a significant reduction in the production of G-CSF by bone marrow stromal cells. HIV leads to a decrease in monocytes in the peripheral blood, resulting in a decline in the secretion level of GM-CSF, which in turn causes a reduction in granulocytes. Finally, it is interesting to note that there was no statistically significant difference in CD4+ lymphocytes between the two groups of patients, but CD19+ lymphocytes were significantly lower in the neutropenia group. This suggests that the humoral immune response in HIV patients is more closely associated with neutropenia, though the specific pathogenesis require further investigation.

In this study, we found that ANC<0.5 × 109/L in PLWHA leads to worse prognosis. Severe neutropenia, coupled with the deterioration of adaptive immunity, significantly elevates the risk of life-threatening secondary infections. Neutropenia serves as a dose-limiting factor for various antimicrobial agents, potentially complicating the management of primary HIV infection and its associated secondary infections [4, 34, 35].Therefore, providing treatment for HIV-positive patients is critical. HIV-positive patients undergoing combination antiretroviral therapy that excludes Zidovudine (AZT), as well as those receiving highly active antiretroviral therapy (HAART) in conjunction with AZT, demonstrate a greater likelihood of resolving neutropenia compared to individuals who are not receiving any form of antiretroviral treatment [36, 37]. Furthermore, various studies have demonstrated that administering Granulocyte Colony-Stimulating Factor (G-CSF) or GM-CSF can effectively counteract myelosuppression, alleviate neutropenia in HIV-infected patients, and substantially reduce the occurrence of severe neutropenia, as well as the rates of bacterial infections and mortality [7, 38, 39].Therefore, early identification and treatment of neutropenia is very important.

Our study has several limitations. First, because all participants underwent bone marrow aspiration, the incidence of neutropenia observed in this cohort may not accurately reflect its prevalence in the entire HIV population. Second, we did not include the patients‘viral load, so their disease status remains unclear. Finally, we performed only statistical analyses of clinical data and did not carry out experimental validation, which we plan to conduct in future research.