Immunologic Interplay Between HIV/AIDS and COVID-19: Adding Fuel to the Flames?

Purpose of Review HIV/AIDS and COVID-19 have been the major pandemics overwhelming our times. Given the enduring immune disfunction featuring people living with HIV (PLWH) despite combination antiretroviral therapy (cART), concerns for higher incidence and severity of SARS-CoV-2 infection as well as for suboptimal responses to the newly developed vaccines in this population arose early during the pandemics. Herein, we discuss the complex interplay between HIV and SARS-CoV-2, with a special focus on the immune responses to SARS-CoV-2 natural infection and vaccination in PLWH. Recent Findings Overall, current literature shows that COVID-19 severity and outcomes may be worse and immune responses to infection or vaccination lower in PLWH with poor CD4 + T-cell counts and/or uncontrolled HIV viremia. Data regarding the risk of post-acute sequelae of SARS-CoV-2 infection (PASC) among PLWH are extremely scarce, yet they seem to suggest a higher incidence of such condition. Summary Scarce immunovirological control appears to be the major driver of weak immune responses to SARS-CoV-2 infection/vaccination and worse COVID-19 outcomes in PLWH. Therefore, such individuals should be prioritized for vaccination and should receive additional vaccine doses. Furthermore, given the potentially higher risk of developing long-term sequelae, PLWH who experienced COVID-19 should be ensured a more careful and prolonged follow-up.


Introduction: HIV/AIDS and COVID-19, a Tale of Two Intersecting Pandemics
HIV/AIDS and COVID-19 have been the major pandemics overwhelming the contemporary era. HIV/AIDS was firstly reported in 1981 in previously healthy young men who developed a life-threatening Pneumocystis carinii (now known as Pneumocystis jirovecii) pneumonia, whose underlying cause was revealed 2 years later to be a retrovirus, which was named human immunodeficiency virus (HIV). Its incidence has been declining since 1996, when protease inhibitors were rolled out for HIV treatment, so that the pandemic may be now considered to have reached an endemic state worldwide [1]. COVID-19 emerged in late 2019 as a severe respiratory disease caused by the quickly identified severe acute respiratory coronavirus 2 (SARS-CoV-2), intersecting the HIV/AIDS pandemics in various ways.
Physicians and medical infrastructures previously dedicated to the care of people living with HIV (PLWH) were reallocated on the frontline in tackling COVID-19 [2]. Inperson clinical visits were discouraged in favor of telemedicine, which is most likely destined to become the standard of care for PLWH with well-controlled infection in the future [3]. Limitations also involved HIV infection laboratory monitoring, as laboratory facilities and personnel were employed in diagnostic testing for SARS-CoV-2. Shortage of medical resources, fear of exposure to SARS-CoV-2, and lockdown restrictions hindered the access to antiretroviral therapy [4]. Overall, notwithstanding different approaches to cope with COVID-19 in PLWH have been put forward in different settings, all the aforementioned elements resulted in a suboptimal care of HIV infection and other comorbidities in PLWH and exacerbated inequalities for key populations affected by HIV [5].
In the meanwhile, given the HIV-driven immune dysfunction also in the course of effective combination antiretroviral therapy (cART), concerns for higher susceptibility of PLWH to SARS-CoV-2 infection and poor COVID-19 outcomes arose, thus leading to prioritize this population for vaccine administration when they became available, albeit the readiness of their immune system to respond to these novel vaccines was unknown at the time. After nearly 3 years into the COVID-19 pandemics, numerous studies aiming to unveil whether PLWH are actually at higher clinical risk have been published, but yielded apparently contradictory findings. Additionally, data assessing how efficiently the immune system of PLWH faces SARS-CoV-2 infection and responds to COVID-19 vaccines remain limited.
In this review, we summarize the knowns and the unknowns of the complex interplay between HIV and SARS-CoV-2 infection, with a special focus on the immune responses to SARS-CoV-2 natural infection and vaccination in PLWH.

Incidence and Clinical Outcome of SARS-CoV-2 Infection in PLWH
An early literature review reported that the prevalence of SARS-CoV-2 infection in PLWH was similar to that observed in the general population [6]. The same study also reported that PLWH accounted for approximately 1.0% of total hospitalized COVID-19 cases [6]. A recent crosssectional study on 4400 consecutive PLWH attending an HIV Clinic in Spain between November 2020 and May 2021 demonstrated that the prevalence of SARS-CoV-2 infection, determined through antibody presence, was 28% [7]. In contrast, recent findings from the EuroSIDA cohort reported positive SARS-CoV-2 PCR results in 122/1026 participants (1.8%) [8]. The different testing procedures and reasons for testing may explain, at least in part, the opposing results.
From a pathogenic standpoint, single-cell transcriptomic analysis across different tissues reported higher co-expression of ACE2 and TMPRSS2 in the lung of HIV-infected humans and in the gut of SHIV-infected non-human primates as compared with uninfected controls [9], suggesting a possible higher risk of SARS-CoV-2 acquisition in PLWH. However, current literature [6,[10][11][12][13] indicates that HIV infection per se is not a risk factor for SARS-CoV-2 infection.
Conflicting data have also emerged in terms of clinical outcome of COVID-19 in the setting of HIV infection. One of the first studies published during the first pandemic wave demonstrated that PLWH were at increased risk of mortality among subjects hospitalized for COVID-19 in the UK [14]. An even higher risk of mortality in PLWH was reported when analyzing data from a large primary care database in the same country [15]. A study from Chile, which was also conducted in the first wave, showed that PLWH were more likely to be admitted to the ICU [16]. In keeping with these results, current findings from the WHO Global Clinical COVID-19 platform, which however mirror data contribution from Africa, showed that HIV infection was an independent risk factor for severe COVID-19 and in-hospital mortality [17]. In this respect, some studies [18], but not others [16], reported poor viro-immunological control as a reason underlying disease severity/mortality in PLWH.
In contrast to the above, research has also demonstrated a similar outcome in PLWH and the general population [19][20][21], highlighting the role of comorbidities in the development of critical COVID-19 [22]. In particular, one study demonstrated a lower rate of ICU admissions, invasive mechanical ventilation, or death in a large cohort of PLWH who were younger than uninfected controls [23]. A recent meta-analysis reported no difference in the risk of death in PLWH compared with the HIV-seronegative population [24].
Taken together, literature published thus far has shown heterogeneity in COVID-19 severity in the context of HIV infection. Age and comorbidities, as well as the lack of viroimmunological control, represent possible risk factors for a worse clinical outcome, and their respective contribution should be assessed in future studies [25•].
Interestingly, some observational studies reported a protective effect of certain antiretroviral drugs, namely tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), against SARS-CoV-2 infection and COVID-19-related outcomes in both PLWH [13,26,27] and HIV pre-exposure prophylaxis (PrEP) users [28,29]. This potential protective effect is biologically plausible due to the ability of nucleotide analog reverse transcriptase inhibitors (NRTIs) to inhibit the SARS-CoV-2 RNA-dependent RNA polymerase [30,31]. However, others did not find such an association [7,32]. These contradictory findings may be the consequence of the baseline characteristics of TDF/FTC-users, which are intrinsically associated with a more favorable outcome of SARS-CoV-2 infection.
Data regarding post-acute sequelae of SARS-CoV-2 infection (PASC) in PLWH are limited. The major risk factors for PASC have been described to be severity of disease, being unvaccinated against SARS-CoV-2, and medical comorbidities [33]. Furthermore, PASC has been associated with a residual inflammation following SARS-CoV-2 infection [34]. Therefore, given the potential for greater risk of COVID-19 severity and reduced responses to SARS-CoV-2 vaccines, and considered the higher burden of comorbidities [35] and the greater baseline levels of immune activation and systemic inflammation [36,37], PLWH may be at higher risk of developing PASC. Actually, the few published studies showed a significantly greater risk of PASC in PLWH when adjusting for other factors, indicating that HIV infection may be an independent risk factor for such condition [38, 39•].

Innate Immune Responses
Type-I interferons (IFNs-I) constitute the first innate immune barrier to SARS-CoV-2 infection at mucosal sites [40]. However, SARS-CoV-2 has evolved several mechanisms to evade such host defense via both its structural and non-structural proteins [41,42]. Moreover, inborn mutations in genes involved in the regulation of IFNs-I immunity, as well as production of auto-antibodies against IFNs-I during COVID-19, have been associated with poor clinical outcome [43,44].
HIV infection triggers interferon responses in the earliest phases, contributing to limit viral replication; nonetheless, persistent exposure to IFNs-I in the chronic phase of HIV infection is associated with desensitization and immune hyperactivation, thus paradoxically contributing to disease progression [45,46].
These observations suggest that complex interactions between the two viruses might influence IFNs-I responses in HIV/SARS-CoV-2 coinfection. An interesting study evaluated the impact of HIV infection on gut epithelial cells susceptible to SARS-CoV-2 infection, showing that chronic-treated HIV infection drives a strong interferon signaling response within absorptive enterocytes, which, however, does not prevent SARS-CoV-2 infection in this compartment [47•] (Fig. 1A). These findings may indicate that the persistent IFNs-I signaling which features chronic HIV infection despite effective cART is not able to confer a protection against SARS-CoV-2 infection. However, the interplay between HIV and SARS-CoV-2 in modulating IFNs-I responses in other anatomical sites, especially the upper respiratory tract which is the site of initial infection, and its role in influencing the susceptibility to SARS-CoV-2 infection in PLWH, have not been characterized and require future research efforts.

Adaptive Immune Responses
Early and robust development of SARS-CoV-2-specific cell-mediated immunity and neutralizing antibodies has been associated to a favorable clinical course of . HIV infection is characterized by a profound disruption of the adaptive immune system, in both its cellular and humoral components, with destruction of CD4 + T-cells, increased CD8 + T-cells, T-cell activation/exhaustion, defective T follicular helper (Tfh) cells activity, and dysfunction and polyclonal activation of B-cells [51,52]. Furthermore, it has recently been demonstrated that SARS-CoV-2 is able to productively infect CD4 + T-cells binding to cell entry receptors other than ACE2 (like LFA-1 and CD147) and to induce their apoptosis which is probably dependent on mitochondria ROS-hypoxia pathways [53••, 54••], suggesting that HIV and SARS-CoV-2 may collide on the immune system. These observations raise the concern that PLWH, especially those with incomplete immune restoration despite virologically effective cART [55], may not appropriately respond to SARS-CoV-2 infection. Thus far, data on adaptive immune responses to natural SARS-CoV-2 infection in this population is limited and, at times, conflicting.
One of the earliest studies in this regard evaluated the T-cell profile in the course of HIV/SARS-CoV-2 coinfection during the first wave of the COVID-19 pandemics, when some PLWH suspended cART due to medication shortages. Compared to SARS-CoV-2 mono-infected individuals, HIV/ SARS-CoV-2-co-infected individuals showed reduced Th1 cells and cytotoxic CD8 + T-cell responses, as well as a higher rate of T-cell exhaustion, which was even more pronounced in those not taking cART [56]. These data suggest a synergic effect of HIV and SARS-CoV-2 on T-cell dysfunction, especially in PLWH with uncontrolled HIV viremia, which may not mount proper immune responses against SARS-CoV-2. A more recent study showed that individuals with unsuppressed HIV infection mount weak antigenspecific CD4 + and CD8 + T-cell responses to SARS-CoV-2 and poorly recognize SARS-CoV-2 beta variant, due to HIVinduced immune defects such as low CD4 + T-cell counts, high HIV plasma viral loads, and elevated immune activation. Yet, virologically suppressed PLWH exhibit SARS-CoV-2-specific T-cell responses similar to those of HIVnegative peers, highlighting the role of uncontrolled HIV infection in hampering immune responses to SARS-CoV-2 and T-cell cross-recognition between viral variants, thus partly explaining the high propensity for severe COVID-19 among PLWH and their vulnerability to emerging SARS- Also, inadequate immune reconstitution on virologically effective cART has been shown to potentially hinder the development of T-cell responses to SARS-CoV-2 infection. Some studies showed that T-cell and humoral responses to SARS-CoV-2 infection do not necessarily move in the same direction. Peluso et al. found that, in the backdrop of similar humoral responses compared to HIV-uninfected individuals, cART-treated PLWH recovering from SARS-CoV-2 infection display high expression of the co-inhibitory receptor PD-1 on SARS-CoV-2-specific memory CD4 + T-cells and low frequencies of specific CD8 + T-cells, suggesting that they may have impaired T-cell functionality upon reencountering infection [39 •]. It has also been reported that although PLWH on effective cART may present lower memory T-cell responses against SARS-CoV-2 as well as dysregulated T follicular helper (Tfh) populations, that is enough to generate a cooperation between T-cells and B-cells that allows to elicit an effective antibody response against the pathogen [61].
Studies evaluating humoral immune responses to SARS-CoV-2 in PLWH also yielded inconsistent observations, probably due to the different demographic and viro-immunological characteristics of study participants, various degree of COVID-19 severity, and sampling during diverse phases post-infection.
Alrubayyi et al. found comparable antibody titers against S1 and N proteins of SARS-CoV-2 in HIV-positive and -negative subjects after mild COVID- 19 [63]. It should be specified that all the studies mentioned above included individuals with wellcontrolled HIV infection.
In sharp contrast, Spinelli et al. found lower RBD-specific IgG concentrations and pseudovirus neutralizing antibodies titers in PLWH with past SARS-CoV-2 infection as compared to HIV-negative individuals [64]. Liu et al. described that in the acute phase of COVID-19, PLWH exhibit a lower IgG seroconversion rate and shorter duration of humoral responses compared to HIV-negative individuals [65]. It must be noted, however, that both studies included also virally unsuppressed people. Accordingly, Khan et al. showed lower neutralization of the Delta variant and a higher frequency of non-responders in PLWH, with the highest frequency of non-responders in those with uncontrolled HIV viremia; furthermore, neutralization activity was correlated with CD4 + T-cell counts, underscoring the importance of both immune recovery and HIV viremia suppression on cART, in influencing humoral immune responses to SARS-CoV-2 [66].
Humoral responses in the convalescent phase of SARS-CoV-2 infection in PLWH may also be influenced by the severity of COVID-19, since antibodies' magnitude and functionality in PLWH have been reported similar to those of people without HIV in the mild (asymptomatic) and severe (symptomatic requiring hospitalization) disease, but diminished in the moderate (symptomatic not requiring hospitalization) disease [67].
Lastly, given that PLWH have been shown to be at higher risk of developing PASC, Peluso et al. explored immunologic features potentially related to such condition in this population, yet no relationships between PASC and SARS-CoV-2-specific humoral and T-cell responses or immune exhaustion were found [39•], suggesting that other factors may be involved in PASC pathogenesis in PLWH.
Taken together, these data indicate that adaptive immune responses to SARS-CoV-2 infection in PLWH are similar to those of the general population overall, but may be less Fig. 1 Immune responses to SARS-CoV-2 infection in PLWH. A Chronic HIV infection on cART drives a strong constitutive IFN-I signaling within absorptive enterocytes in the small intestine, which, however, is not able to prevent SARS-CoV-2 infection in this compartment. The interplay between HIV and SARS-CoV-2 in modulating IFNs-I responses in other anatomical sites, especially the respiratory tract, which is the site of initial infection, is currently unknown. B PLWH with well-controlled HIV infection mount adaptive immune responses comparable to those of people without HIV. Yet, PLWH with low CD4 + T-cell counts and/or detectable HIV viremia develop suboptimal immune responses to SARS-CoV-2 infection (fewer and exhausted SARS-CoV-2-specific T-cells, impaired T-cell cross recognition of VOCs, lower SARS-CoV-2-specific B-cells and neutralizing antibodies). C HIV infection is associated with enduring systemic inflammation and immune activation despite effective cART; on the other side, in absence of cART, HIV infection leads to immune suppression, mainly-albeit not only-driven by the depletion of CD4 + T-cells. Whether such features of HIV infection may exacerbate or hinder the COVID-19-related cytokine storm is currently unknown, as the few available data are conflicting. D PLWH with low CD4 + T-cell counts may have a delayed SARS-CoV-2 clearance due to the immune defects. The subsequent prolonged viral replication (sustained by the RNA-dependent RNA-polymerase) can lead to the emergence of multiple mutations and thus to the development of new viral variants escaping from antibody neutralization. PLWH, people living with HIV; cART , combination antiretroviral therapy; IFN-I, type-I interferon; VOCs, variants of concern. Created with BioRender. com ◂ efficient in the setting of scarce immune recovery and uncontrolled HIV viremia (Fig. 1B).

Inflammation
HIV infection elicits a chronic hyperinflammatory state that persists despite effective cART [36,37], sharing inflammatory markers that have been also described as elevated in severe COVID-19, such as IL-6 and TNF-α [49]. Given these premises, it can be speculated that HIV may exacerbate COVID-19-related cytokine storm and thus severity, leading to unfavorable outcomes. On the other hand, it may be assumed that PLWH can be protected from hyper-activation/ inflammation-mediated immunopathology due to the HIVdriven immune defects. As described in HIV-negative individuals [50], PLWH hospitalized for COVID-19 have been shown capable of mounting a profound inflammatory reaction in response to SARS-CoV-2 coinfection that is higher in fatal cases [68]. While some studies reported lower levels of inflammatory markers such as IL-6, TNF-α, and IL-8 in PLWH as compared to the HIV-negative counterpart [61, 69], another study found higher IL-6, TNF-α, and IP-10 in HIV/SARS-CoV-2-coinfected individuals [39•]. Hence, whether immune imbalances which feature chronic HIV infection may enhance or hinder the COVID-19-related cytokine storm is yet to be determined (Fig. 1C).

Delayed Clearance of SARS-CoV-2 and Immune Escape
Low CD4 + T-cell counts in PLWH can potentially hamper SARS-CoV-2 clearance, as suggested by a murine model of acute SARS-CoV-2 infection, in which depletion of CD4 + T-cells led to reduced antibody response and delayed viral clearance [70]. Prolonged infections may allow SARS-CoV-2 to evolve diverse resistance mutations, since it mutates at a relatively slow rate compared to other RNA viruses due to its proof-reading mechanism [71]. Actually-as previously described in patients with immune suppression due to other causes [72][73][74]-several cases of prolonged SARS-CoV-2 infection have been reported in PLWH with severe T-cell depletion and/or AIDS, with subsequent emergence of a multitude of mutations conferring extensive escape from antibody neutralization elicited by both ancestral SARS-CoV-2 infection and vaccines [18, 75••, 76, 77] (Fig. 1D).

SARS-CoV-2 Vaccine Efficacy and Safety in PLWH
When SARS-CoV-2 vaccines were rolled out, PLWH-especially those with current CD4 + T-cell count < 200/μL, evidence of an opportunistic infection, and/or with a detectable viral load-were prioritized for vaccination, due to the potential higher risk for worse COVID-19 outcomes [78].
Given that suboptimal and less durable immune responses to several vaccines have been reported in PLWH, particularly in those with scarce immune recovery despite cART [79][80][81][82], concerns were raised about immunogenicity and clinical efficacy of these vaccines in this potentially more vulnerable population.
Unfortunately, the larger phase 2/3 SARS-CoV-2 vaccine clinical trials included few PLWH (176 for mRNA-1273, 196 for BNT162b2, and 107 for ChAdOx1-S), therefore lacking to report efficacy, safety, and immunogenicity for this sub-population [83][84][85]. Additionally, there are no head-to-head comparisons between different COVID-19 vaccines in PLWH thus far; hence, whether a certain vaccine platform is more effective and should therefore be preferred in this population is currently unknown. Furthermore, data on vaccine-induced protection against emerging variants of concern (VOCs) in this population are also lacking and should be addressed by future research.
Nonetheless, two large longitudinal studies carried out in the USA found a higher rate of breakthrough infections in fully vaccinated PLWH [86,87]; however, among them, high CD4 + T-cell counts (> 500/μL) and having received an additional dose were associated with a reduced risk [86]. These data clearly suggest that the clinical efficacy of the primary vaccine cycle may be inferior in PLWH, especially in those with low CD4 + T-cell counts, who should therefore receive additional doses.
Risk of severe side effects to SARS-CoV-2 vaccines has not been reported to be higher in PLWH than in general population. However, HIV viral blips after SARS-CoV-2 vaccination were described in some PLWH with low CD4 + T-cell nadir and/or high HIV-RNA zenith [88,89]. Previous studies have found transient increases in HIV viral load with other vaccines, including HBV, influenza, and Streptococcus pneumoniae [90][91][92], which typically occurs within 7-14 days post-vaccination [93]. Such phenomenon may be attributed to a reactivation of the latent HIV reservoir, probably due to a vaccine-elicited generalized inflammatory response with cytokine production able to activate bystander cells harboring latent HIV, rather than the solely activation of HIV-infected vaccinespecific T-cells [93]. In this context, the increased HIV transcription is accompanied by enhanced HIV-specific CD8 + T-cell responses, pointing to standard vaccines as a potential tool to reverse HIV latency to enable eradication by cytotoxic T-cells [93]. Accordingly, a recent study showed that BNT162b2 vaccine activates the RIG-I/ TLR-TNF-NFkB axis, resulting in transcription of HIV proviruses; in parallel, Nef-specific CD8 + T-cells increase and acquire cytotoxic effector functions, which correlate , suggesting that they may benefit from additional vaccine doses. In this respect, a third dose of a mRNA vaccine following the primary cycle has been shown to strongly boost humoral albeit not T-cell responses in PLWH with advanced disease at the time of HIV diagnosis (CD4 + T-cells < 200/μL and/ or AIDS), irrespective of the current CD4 + T-cell count [102••]. Furthermore, PLWH with a current CD4 + T-cell count < 250/μL retain a similar neutralization activity against Delta variant, yet reduced against Beta [103].
In accordance with these findings, we have recently shown that in PLWH with pre-cART advanced immunodeficiency and full virologic control on cART, a 2-dose mRNA-1273 vaccine cycle is able to induce spike-specific memory polyfunctional T helper 1 (Th1) and T follicular helper (Tfh) cells as well as anti-RBD antibodies capable of inhibiting the spike-ACE2 binding. Such vaccineelicited immune responses, which are still detectable after 6 months from vaccination, are not inferior to those of HIV-negative peers, albeit a positive correlation between humoral responses and CD4 + T-cell recovery on cART were found [104]. As regard adenoviral vector vaccines (ChAdOx1-S and Ad26.COV2.S), no significant differences were found in magnitude and durability of vaccine-induced humoral and T-cell responses based on HIV status [66, 105 ••, 106]. PLWH also show ChAdO1x-S-elicited cross-reactive binding antibodies to the Beta variant; furthermore, those who develop high-titre responses also retain neutralization activity against Beta [107]. PLWH with well-controlled HIV vaccinated with Ad26.COV2.S display similar neutralization response of the Delta variant as compared to people without HIV [66]. However, immunogenicity of such vaccines in PLWH with lower CD4 + T-cell counts has not been evaluated.
A comparison between the immunogenicity of different vaccine platforms in PLWH has been reported in some studies. mRNA vaccines appear to elicit the highest immune responses in this population [113-115, 116•, 117]. Among mRNA vaccines, BNT162b2 has been show less immunogenic than mRNA-1273 [100, 102••, 118]. However, given the lack of immune thresholds that correlate to protection after vaccination, the clinical significance of such lower immunogenicity is currently unknown. Nonetheless, in light of these data and awaiting future clarifications on their clinical relevance, mRNA vaccines should be preferred in PLWH [119].
Some studies reported higher immune responses to both mRNA and adenoviral vector COVID-19 vaccines in PLWH with previous SARS-CoV-2 infection [107,118,120] or preexisting cross-reactive T-cell responses correlated with prior exposure to seasonal coronaviruses [106], suggesting that, similar to what observed in the general population, a preexisting immune memory may boost immune responses to COVID-19 vaccines.
Lastly, similarly to HIV-negative individuals [121,122], PLWH show waning antibody immunity (especially against VOCs), yet persistent T-cell responses 6 months post-vaccination [123•], pointing to a potential role of vaccine-elicited cellular immune memory in ensuring a long-term protection.
The main findings of the major studies evaluating immune responses to different SARS-CoV-2 vaccine platforms in PLWH are summarized in Table 1.

Concluding Remarks
COVID-19 pandemics posed a serious threat to public health and collided with HIV/AIDS, leading to a suboptimal care of PLWH worldwide. Nevertheless, concerns for higher susceptibility of PLWH to SARS-CoV-2 infection and poor COVID-19 outcomes arose, thus leading to prioritize this population for vaccination. Additionally, given the enduring immune dysfunction which features chronic HIV infection despite effective cART, PLWH have been considered at risk of lower and less functional immune responses to SARS-CoV-2 natural infection and vaccination, with potentially negative implications for disease outcomes and vaccines efficacy.
Despite such concerns, current knowledge, albeit not granular and at times apparently conflicting, is somehow reassuring for PLWH with well-controlled HIV infection. Immune responses to both SARS-CoV-2 natural infection and vaccination in PLWH have been shown similar to those of people without HIV, with the only exception of those with low CD4 + T-cell counts and/or uncontrolled HIV viremia, who may indeed develop suboptimal T-cell and humoral immune memory following infection and vaccination (Fig. 2). Accordingly, COVID-19 severity and outcomes in this population seem to be worse especially in the presence of concurrent age-related comorbidities and in case of severe CD4 + T-cells depletion, a condition which also potentially increase the risk of breakthrough infections after the primary vaccine cycle, suggesting a suboptimal immune response to vaccination. Data regarding the risk of PASC among PLWH are extremely scarce, yet seemingly indicative of a higher incidence, albeit whether immune factors are involved in its pathogenesis and whether it can negatively impact the immunologic landscape of chronic HIV infection in the long run is yet to be determined.
Altogether, these data clearly support the need for additional vaccine doses in PLWH with ongoing HIV replication and/or scarce immune reconstitution despite virally effective cART. Furthermore, given the potentially higher risk of developing long-term sequelae, PLWH who experienced COVID-19 should be ensured a more careful and prolonged follow-up, in order to avoid adding the PASC fuel to the HIV crackling flames.
Funding Open access funding provided by Università degli Studi di Milano within the CRUI-CARE Agreement. This work was supported by grants from Fondazione Cariplo in collaboration with Regione Lombardia and Fondazione Umberto Veronesi (CAR_RIC20GMARC_01 and CAR_RIC20GMARC_02) and by Fondazione di Comunità Milano (FON_NAZ20ADARM_01).

Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.

Conflict of Interest
The authors declare no competing interests.
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