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Loss of Preexisting Immunological Memory Among Human Immunodeficiency Virus-Infected Women Despite Immune Reconstitution With Antiretroviral Therapy
 
 
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Despite effective immune reconstitution with ART, the loss of immunological memory to prior infections or vaccinations may play a previously overlooked role in the chronic inflammation and "accelerated aging" observed among HIV-infected individuals [3]. These data suggest that despite successful use of ART, HIV infection is associated with a significant loss in virus-specific CD4+ T-cell memory and antiviral antibody responses that may leave a sizeable proportion of HIV-infected people at increased risk for virus-associated disease manifestations. CONCLUSION: Despite antiretroviral therapy-associated improvement in CD4+ T-cell counts (nadir, <200/μL; >350/μL after antiretroviral therapy), antigen-specific CD4+ T-cell memory to vaccinations or infections that occurred before HIV infection did not recover after immune reconstitution, and a previously unrealized decline in preexisting antibody responses was observed.
 
The current study has several limitations. We examined immunological memory among HIV-infected individuals who had a CD4+ T-cell count nadir of <200/μL that reconstituted to >350/μL after ART. Although these levels seem adequate to describe a population experiencing severe immunologic damage and significant recovery, additional studies will be needed to determine whether those with a higher nadir or with greater recovery (ie, counts >500/μL) are likely to demonstrate loss of CD4+ T-cell memory (Figure 2) or rapid decline in preexisting antibody responses (Figure 3). As with any long-term cohort study, a proportion of participants are lost to follow-up, owing to death or attrition, and it is unknown if this may affect study results. In addition, the initial study focused on HIV-infected women, and further studies among HIV-infected men are warranted.
 
Abstract
 
Background

 
It is unclear whether human immunodeficiency virus (HIV) infection results in permanent loss of T-cell memory or if it affects preexisting antibodies to childhood vaccinations or infections.
 
Methods
 
We conducted a matched cohort study involving 50 pairs of HIV-infected and HIV-uninfected women. Total memory T-cell responses were measured after anti-CD3 or vaccinia virus (VV) stimulation to measure T cells elicited after childhood smallpox vaccination. VV-specific antibodies were measured by means of enzyme-linked immunosorbent assay (ELISA).
 
Inclusion criteria for HIV-infected women included selection of individuals who were born before 1971 and were seropositive at baseline against VV (>200 enzyme-linked immunosorbent assay [ELISA] units), had started ART ≤5 years after joining the study, and had a CD4+ T-cell count nadir <200/μL that improved to >350/ μL after administration of ART. Elite controllers and seroconverters with primary HIV infection were excluded from this study to focus immunological analysis on HIV-infected participants with chronic HIV infection in which immune reconstitution was achieved by ART.
 
Results
 
There was no difference between HIV-infected and HIV-uninfected study participants in terms of CD4+ T-cell responses after anti-CD3 stimulation (P = .19) although HIV-infected participants had significantly higher CD8+ T-cell responses (P = .03). In contrast, there was a significant loss in VV-specific CD4+ T-cell memory among HIV-infected participants (P = .04) whereas antiviral CD8+ T-cell memory remained intact (P > .99). VV-specific antibodies were maintained indefinitely among HIV-uninfected participants (half-life, infinity; 95% confidence interval, 309 years to infinity) but declined rapidly among HIV-infected participants (half-life; 39 years; 24-108 years; P = .001).
 
The frequency of VV-specific memory CD8+ T cells was determined within the same assays (Figure 2C). The frequency of VV-specific memory CD8+ T cells among the HIV-uninfected cohort was estimated at 40 per 106 CD8+ T cells (median, 34; range, 20-66), similar to the mean frequency of 61 virus-specific CD8+ T cells per 106 CD8+ T cells (median, 32; range, 21-166) among the HIV-infected cohort. Unlike the virus-specific CD4+ T-cell responses, there was no significant difference between the percentage of HIV-uninfected or HIV-infected participants who maintained antiviral CD8+ T-cell memory (15% vs 12%, respectively; P > .99, exact McNemar test) (Figure 2D). This indicates that after HIV infection and successful immune reconstitution after ART, preexisting CD8+ T-cell memory to an unrelated infection encountered during childhood (VV) seemed to remain intact, whereas preexisting CD4+ T-cell memory to the same pathogen was preferentially lost despite normal numbers of functional CD4+ T cells in circulation (Figure 1).
 
Unlike their HIV-uninfected counterparts, these studies indicate that 1 in every 5 HIV-infected participants are prone to an accelerated loss of serological memory despite successful immune reconstitution by ART.
 
Conclusions
 
Despite antiretroviral therapy-associated improvement in CD4+ T-cell counts (nadir, <200/μL; >350/μL after antiretroviral therapy), antigen-specific CD4+ T-cell memory to vaccinations or infections that occurred before HIV infection did not recover after immune reconstitution, and a previously unrealized decline in preexisting antibody responses was observed.
 
23 December 2019 JID - Archana Thomas,1 Erika Hammarlund,1 Lina Gao,2 Susan Holman,3 Katherine G. Michel,4 Marshall Glesby,5 Maria C. Villacres,6 Elizabeth T. Golub,7 Nadia R. Roan,8 Audrey L. French,9 Michael H. Augenbraun,3,a and Mark K. Slifka1,a 1Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA, 2Biostatistics Shared Resource, Knight Cancer Institute, Biostatistics & Bioinformatics Core, Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon, USA, 3Division of Infectious Diseases, Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, New York, USA, 4Department of Medicine, Georgetown University Medical Center, Washington, DC, USA, 5Division of Infectious
 
Diseases, Department of Medicine, Weill Cornell Medical College of Cornell University, New York, New York, USA, 6Department of Pediatrics, Keck School of Medicine of USC, Los Angeles, California, USA, 7Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA, 8Department of Urology, University of California, San Francisco, San Francisco, California, USA, 9Department of Medicine, Cook County Health and Hospitals System, Chicago, Illinois, USA
 
DISCUSSION
 
We examined the durability of antiviral T-cell and antibody responses after childhood smallpox vaccination as a model to determine the impact of HIV and ART on the maintenance of preexisting immunological memory in the absence of reexposure or revaccination. After ART-associated immune reconstitution, HIV-infected women showed no reduction in the percentage of functional, anti-CD3-responsive CD4+ T cells. However, when antigen-specific assays were used to study immunity from smallpox vaccination, we found a nearly complete loss of VV-specific CD4+ T-cell memory even though CD8+ T-cell responses remained largely unchanged compared with HIV-uninfected controls. Analysis of VV-specific antibody responses revealed a significant decline in serological memory despite successful ART-associated maintenance of peripheral CD4+ T cells. The loss of CD4+ T-cell memory and antibody responses to infections encountered before HIV acquisition could have implications with regard to protective immunity to common acute or chronic viral infections.
 
CD4+ T-cell-mediated cytokine responses after polyclonal anti-CD3 stimulation did not differ significantly between HIV-infected women or HIV-uninfected controls (P = .19) (Figure 1). In contrast, anti-CD3-responsive CD8+ T-cell responses were significantly up-regulated among the HIV-infected cohort (P = .03). These results are consistent with findings of prior studies in which polyclonal stimulation of peripheral T cells from HIV-infected participants showed that CD4+ T-cell responses were equal to or lower than those in HIV-uninfected controls, whereas CD8+ T-cell responses were consistently higher among HIV-infected cohorts [32-34]. Although the reason for increased CD8+ T-cell responses among HIV-infected participants remains unclear, it is believed that immune activation may be due to a decreased ability to control repeated or chronic viral infections, resulting in a state of persistent inflammation and an "inflammaging" phenotype [3].
 
In our hands, VV-specific memory CD8+ T-cell responses observed among HIV-infected women seemed similar to those observed among HIV-uninfected women in terms of the overall magnitude of the remaining memory T-cell response per participant (Figure 2C) and the proportion of participants who maintained a detectable CD8+ memory T-cell response (Figure 2D). One challenge with interpreting these studies is the low frequency of T-cell memory identified at late time points examined decades after acute VV infection [19], and more studies are needed to determine whether the persistent inflammation and inflammaging phenotype observed among HIV-infected participants might contribute to a more stable frequency of preexisting CD8+ memory T cells or whether the increased frequency of CD8+ T cells with a functional memory phenotype (Figure 1B) is due to recruitment of new T cells into the memory T-cell pool.
 
Prior studies have indicated that antigen-specific T-cell memory after HIV acquisition and subsequent administration of ART was either lost [5-7] or restored [5, 8-10]. In some cases, the restoration of antigen-specific T-cell responses is likely due to antigenic reexposure after ART (eg, cytomegalovirus, herpes simplex virus, and Candida albicans) [5, 8, 9]. One study showed, lymphoproliferative responses to tetanus toxoid were restored regardless of booster immunization [10]. In another study [9], lymphoproliferative responses to purified protein derivative, influenza, and tetanus toxoid remained persistently weak even after ART. The CD4+ T-cell nadir before ART may influence immune reconstitution, because vaccine-induced CD4+ T-cell memory did not recover among HIV-infected participants with a low CD4+ T-cell nadir of ≤350/μL, whereas those with CD4+ T-cell counts remaining above 350/μL had memory CD4+ T-cell responses that remained intact [6].
 
In our current studies, we examined the recall responses to VV antigens that are unlikely to be encountered after cessation of routine smallpox vaccination among civilians born after 1972. We enrolled HIV-infected participants who had a CD4+ T-cell nadir of <200/μL that rebounded to >350/μL after ART and found that CD4+ T-cell memory was lost among HIV-infected participants, whereas antiviral CD8+ T-cell memory remained intact (Figure 2). Because CD8+ T-cell responses were determined in the same assays as the CD4+ T-cell responses, this indicates that differences between groups are unlikely to be due to any technical issues or cohort effects and that CD8+ T-cell memory is preferentially retained over CD4+ T-cell memory after HIV acquisition and ART.
 
Poor antibody responses to vaccination among HIV-infected individuals have been well described [28, 35, 36]. Much less is known about the impact of HIV/ART on the maintenance of preexisting humoral immunity. One study showed, antibody responses to tetanus were maintained among 7 HIV-infected participants taking ART, with a mean half-life of 11 years [11], similar to previous findings in the general population [23, 37]. Differences in antibody decay rates may not have been observed in this small cohort if the most rapid antibody decay rates occur among only 20% of the HIV-infected population, as observed in our study (Figure 3). Alternatively, the antibody decay rates could be different for particular virus or vaccine antigens. One study observed a nonsignificant trend toward more rapid measles antibody decay rates during primary HIV infection [12], but when monitored longitudinally during the chronic phase of infection, the antibody responses seemed stable. However, these longitudinal studies measured just a 24-month span of time, making it difficult to identify broader differences in long-term antibody maintenance. Further studies are needed to determine whether rapid loss of serological memory among HIV-infected participants is unique to specific viruses or vaccine antigens or whether it represents a more global defect in immune memory among these individuals. For instance, the overall rate of herpes zoster from varicella zoster virus among HIV-infected adults is nearly 4-fold higher than that observed in the general US population [2]. HIV infection is also associated with higher rates of virus-related cancers, including Kaposi sarcoma (human herpesvirus 8), lymphomas (Epstein-Barr virus), anal cancer (human papillomavirus), and liver cancer (hepatitis B and hepatitis C virus). In contrast, there is no association between HIV infection and an increased risk of non-virus-associated cancers, such as breast, prostate, or colorectal cancer [3]. After the introduction of highly active ART, the incidence of certain virus-associated cancers such Kaposi sarcoma and non-Hodgkin lymphoma decreased, whereas the incidence of cervical cancer remained largely unaltered [38], indicating that prolonged immune suppression plays a role in susceptibility to some pathogens but may not completely explain the increased risks associated with HIV infection.
 
The loss in preexisting serological memory among HIV-infected participants is likely due to the loss of long-lived antibody-secreting plasma cells [39], most of which reside in the bone marrow. Bone and bone marrow abnormalities that may occur after HIV infection or ART include osteoporosis, osteopenia, osteomalacia, osteonecrosis, low bone marrow density, and increased risk of fractures [40]. In addition, HIV infection leads to depletion of hematopoietic progenitor cells [41] and senescence of bone marrow mesenchymal stem cells, resulting in reduced support of hematopoietic stem cells in vitro [42]. HIV infects bone marrow stromal cells and HIV glycoprotein 120 and Gag p55 have been shown to be involved with bone disorders [40]. Moreover, HIV therapies involving tenofovir disoproxil fumurate and protease inhibitors have been directly associated with bone abnormalities [40]. It is possible that HIV, ART, or a combination of these factors may lead to disruption of the bone marrow microenvironment needed to sustain plasma cell survival and long-term antibody responses.
 
The current study has several limitations. We examined immunological memory among HIV-infected individuals who had a CD4+ T-cell count nadir of <200/μL that reconstituted to >350/μL after ART. Although these levels seem adequate to describe a population experiencing severe immunologic damage and significant recovery, additional studies will be needed to determine whether those with a higher nadir or with greater recovery (ie, counts >500/μL) are likely to demonstrate loss of CD4+ T-cell memory (Figure 2) or rapid decline in preexisting antibody responses (Figure 3). As with any long-term cohort study, a proportion of participants are lost to follow-up, owing to death or attrition, and it is unknown if this may affect study results. In addition, the initial study focused on HIV-infected women, and further studies among HIV-infected men are warranted.
 
Despite effective immune reconstitution with ART, the loss of immunological memory to prior infections or vaccinations may play a previously overlooked role in the chronic inflammation and "accelerated aging" observed among HIV-infected individuals [3]. These data suggest that despite successful use of ART, HIV infection is associated with a significant loss in virus-specific CD4+ T-cell memory and antiviral antibody responses that may leave a sizeable proportion of HIV-infected people at increased risk for virus-associated disease manifestations.

 
 
 
 
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