There are relevant similarities between HIV and SARS-CoV–2 viruses. They are both RNA virus, able to cross species barriers and to transmit to humans, causing zoonotic diseases. Pandemic diffusion of these viruses has impacted people all over the world, spreading fear and uncertainty in the general population . In addition, it has been reported that SARS-CoV–2 can infect T lymphocytes, the same cells targeted by HIV  and individuals with severe SARS-CoV–2 infection may exhibit lymphopenia just like HIV infected patients .
Lymphocyte subset analysis using monoclonal antibodies and FCA is a powerful tool. The evaluation of the immunophenotypic profile of a patient (i.e., the number of different types of lymphocytes determined by flow cytometry) is currently used in immunodeficiencies, leukemias and lymphomas as well as in post-transplanted patients. FCA has proved to be essential in providing information on the T cell CD4+ subset reduction, which is considered the laboratorial hallmark of the evolution of HIV infection as well as an indicator, together with clinical evidence of HIV infection, for the commencement of antiretroviral therapy. FCA provides the health care professional with information about the relative and absolute population of immune subtypes in the blood and has become the gold standard in estimating CD4+ counts for both diagnosis and monitoring of the response to therapy in HIV-infected patients. CD4+ T cells, in fact, are central mediators of immune response in humans. They play a crucial role in coordinating cellular and humoral immune responses against infections. The gradual loss of CD4+ T cells represents the hallmark of HIV and the consequent progressive impairment of immunity constitutes also a relevant cause of death in these patients.
It has been previously reported that the main difference in lymphoid phenotypes observed in HIV- infected patients is a reduction by 40% in the CD4+ T helper population and a 45% increase in the CD8+ cytotoxic T-cell population . However, despite decades of experimental research, the complete mechanism of CD4+ T depletion in HIV infection still remains to be explained .
Growing amounts of data have accumulated and are available regarding the immune response in patients affected by COVID–19. Dysregulation of immune response, especially in T lymphocytes, are frequently observed in SARS-CoV–2 infection and might be highly involved in the pathological process of COVID–19. The common feature consisted, in fact, in lymphopenia, which can be severe and progressive in some patients, mostly the more severely affected and those with fatal illnesses [3,12]. In another study in which the COVID–19 patients have been stratified according their disease severity and data have been crossed with the composition of immune cells, an inverse correlation between disease severity and percentage of lymphocytes has been reported . The same inverse correlation was reported with CD8+ T cells too . There is evidence of an exuberant inflammatory response, similar to cytokine release syndrome, which was defined as “cytokine storm syndrome” .
The analysis of the lymphocyte subsets by flow cytometry represents an essential help in the early screening, diagnosis and treatment of COVID–19. The total number of B cells, T cells and NK cells are significantly decreased in patients with COVID–19 and such reduction is more evident in the severe cases compared to the non-severe ones. In patients with COVID–19 both helper T cells (CD4+) and suppressor T cells (CD8+) have been reported to be below normal levels, and the decline of helper T cells was more pronounced in severe cases.
The major difference that we have observed in our two groups of patients consists in the different number of T cells, analyzed by FCA. The HIV patients showed a marked reduction in the CD4+ T cells and a consequent reduction in the CD4+/CD8+ ratio. Surprisingly, a comparable reduction in the CD4+ T cell population is observed also in COVID–19 patients, with no statistically significant difference between the two diseases. In COVID–19 patients, the CD4+ reduction is associated with a marked reduction in the CD8+ T cell population. As a consequence, the CD4+/CD8+ ratio is increased compared to normal values and much higher when compared to HIV patients.
The most evident difference between COVID–19 and AIDS is related to the absolute count of CD8+ T cells. The total number of the CD8+ T cell subpopulations, in fact, is strikingly different in the two groups of patients. In our HIV patients the CD8+ T cells are slightly increased, with respect to the normal value. In this regard, a remarkable expansion of CD8+CD28-CD127loCD39+ Treg cells, that correlates with HIV viremia, has been previously reported . The total number of these cells correlates also with the clinical course of the disease and, in particular, with signs of chronic immune cell activation and with immunodeficiency events. Conversely, in our COVID–19 patients, the level of CD8+ T cells is markedly reduced. We are not able to confirm these data in our patients because they have not been evaluated using antibodies directed against the Treg cell population or their subgroups, namely the naïve-resting cells (CD45RA+) and the memory-activated cells (CD45RA−). In both virus infections, the exact reason of the reduction in the lymphocyte numbers in the blood is not clearly defined yet and many hypotheses have been proposed [11,16]. In particular, it is not clear whether the reduction in the serum levels of T cells is due to an imbalance between production of T- cells and increased apoptosis of CD4+ T cells by viral attack the so-called of “accelerated destruction” hypothesis. Another possibility is that the CD4+ depletion could be due to an accelerated turnover of the CD4+ T cells, with increased production of activated CD4+ T cells characterized by a very short life span. These cells are lost rather quickly due to activation-induced cell death or apoptosis, the so- called “hyper immune activation hypothesis”. Another hypothesis is that the gradual loss of peripheral CD4+ T cells, observed during HIV infection, could be due to a massive production of proinflammatory cytokines, the so-called “cytokine storm”, that has deleterious effects on CD4+ T cells, thus leading to their clonal deletion. In addition, the occurrence of a highly inflammatory form of programmed cell death, called pyroptosis has been involved. In this type of apoptosis, the dying cell releases all its cytoplasmic contents, including inflammatory cytokines that, in turn, trigger pyroptosis in other T-cells as part of a vicious cycle of abortive T cell depletion. Finally, CD4 depletion has been associated with a relative expansion of Treg cells, irrespective of the presence or absence of circulating virus .
The depletion of CD4+ T cells may also be due to an altered lymphocyte trafficking . In the case of HIV, it has been suggested that the depletion of CD4 lymphocytes could be due to an increased CD4+ lymphocyte homing rates , but the mechanism is not fully elucidated yet.
A clue to help in resolving this question may derive from the use of whole-body positron emission tomography (PET). The 18F-FDG PET/CT scanning has been demonstrated to be of benefit in determining the location and severity of disease activity in many inflammatory disorders . It has been used in AIDS patients in search of specific sites of immune activation. Upon HIV infection, resting lymphocytes are activated and switch to glycolysis, increasing their glucose uptake by around 20-fold over 24 hours [21,22]. In 2003, Alexander M Scharko et al. reported their attempts to identify the specific immune-system activation in response to HIV infection . A total of 15 patients were analyzed in different stages of the disease. According to this study HIV–1 is able to induce activation of distinct lymphoid tissues according to the stages of the disease. When the analysis was performed in the acute stage, PET imaging showed that activated lymphoid tissues was localized in the head and neck, with some splenic involvement. Mid stages of the disease are associated with a more generalized pattern of peripheral lymph-node activation. Finally, during the late stages of the disease an involvement of abdominal lymph nodes was more evident. This study demonstrated that whole- body FDG PET images of HIV-positive patients present a clear association between the pattern of lymphoid tissue activation and HIV progression. Unfortunately, no study has been published so far concerning the pattern of PET imaging in COVID–19 patients.
Another relevant observation is related to the reduced number of NK cells, observed in both COVID- 19 and AIDS patients. NK cells play a fundamental role in the immune response, bridging the innate and adaptive immune systems. In particular, they are considered the antiviral effectors of the innate immune system. NK cells, in fact, are capable to directly respond to viruses, to develop memory-like responses after initial pathogen encounter or vaccination, and to shape the adaptive immune response. The role on NK cells in HIV infection has been recently reviewed  and these cells are gaining consideration in COVID–19 too . The absolute number of NK cells is reduced in both our AIDS and COVID–19 patients. However, we observe a more severe reduction of NK cells in COVID–19 patients compared to AIDS ones. The meaning of this difference and the exact role of NK in HIV as well as in SARS-CoV–2 infections needs to be elucidated yet.