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Despite ART/Faster Immune Aging in HIV+
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Loss of Pre-Existing Immunological Memory among HIV Infected Women Despite Immune Reconstitution with Antiretroviral Therapy. Dec 2019
Despite effective immune reconstitution with ART, the loss of immunological memory to prior infections/vaccinations may play a previously overlooked role in chronic inflammation and "accelerated aging" observed among HIV+ 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+ people at increased risk for virus-associated disease manifestations. ....The loss of CD4+ T cell memory and antibody responses to infections encountered prior to HIV acquisition could have implications with regard to protective immunity to common acute or chronic viral infections. ......We enrolled HIV+ subjects who had CD4 nadir <200/mm3 that rebounded to >350/mm3 after ART and found that CD4+ T cell memory was lost among HIV+ subjects whereas antiviral CD8+ T cell memory remained intact (Fig. 2). Since 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 instead indicates that CD8+ T cell memory is preferentially retained over CD4+ T cell memory after HIV acquisition and ART. ......These results are consistent with prior studies in which polyclonal stimulation of peripheral T cells from HIV+ subjects showed that CD4+ T cell responses were equal to or lower than HIV- controls whereas CD8+ T cell responses were consistently higher among HIV+ cohorts[32-34]. Although the reason for increased CD8+ T cell responses among HIV+ subjects 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]. .......After the introduction of HAART, the incidence of certain virus-associated cancers such KS and NHL decreased whereas cervical cancer incidence 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 pre-existing serological memory among HIV+ subjects 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/ART include osteoporosis, osteopenia, osteomalacia, osteonecrosis, low bone marrow density, and increased risk of fractures.
Summary:
Despite successful immune reconstitution following antiretroviral therapy (ART), virus-specific CD4+ T cell memory and antiviral antibody responses following childhood smallpox vaccination were found to be preferentially lost among HIV+ women compared to matched HIV- controls..... there was a significant loss in vaccinia-specific CD4+ T cell memory among HIV+ subjects (P=0.039) whereas antiviral CD8+ T cell memory remained intact (P=1.0). Vaccinia-specific antibodies were maintained indefinitely among HIV- subjects (half-life; infinity, 95%CI, 309 years-infinity) but declined rapidly among HIV+ subjects (half-life; 39 years, 95%CI, 24-108 years, P=0.001). Despite ART-associated improvement in CD4+ T cell counts (nadir CD4 <200 cells/mm3 with >350 cells/mm3 after ART), antigen-specific CD4+ T cell memory to vaccinations/infections that occurred before HIV infection did not recover after immune reconstitution and a previously unrealized decline in pre-existing antibody responses was observed.....Some studies indicate that pre-existing antigen-specific T cell memory is either lost[5-7] or restored[5, 8-10] after ART-associated immune reconstitution. ....Since HIV+ individuals often demonstrate immunological characteristics that are more commonly associated with an aging immune system[13], this raises questions regarding whether HIV infection exacerbates immune senescence in part by decreasing protective immunological memory to vaccinations or infections that occurred in the distant past. ......Analysis of vaccinia-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 prior to HIV acquisition could have implications with regard to protective immunity to common acute or chronic viral infections. .....These results are consistent with prior studies in which polyclonal stimulation of peripheral T cells from HIV+ subjects showed that CD4+ T cell responses were equal to or lower than HIV- controls whereas CD8+ T cell responses were consistently higher among HIV+ cohorts[32-34]. Although the reason for increased CD8+ T cell responses among HIV+ subjects 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]. .......After the introduction of HAART, the incidence of certain virus-associated cancers such KS and NHL decreased whereas cervical cancer incidence 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 pre-existing serological memory among HIV+ subjects 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/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 gp120 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 the two may lead to disruption of the bone marrow microenvironment needed to sustain plasma cell survival and long-term antibody responses.
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Accepted manuscript
Loss of Pre-Existing Immunological Memory among HIV Infected Women Despite Immune Reconstitution with Antiretroviral Therapy
JID Dec 2019 - Archana Thomas1, Erika Hammarlund1, Lina Gao2, Susan Holman3, Katherine G. Michel4, Marshall Glesby5, Maria C. Villacres6, Elizabeth T. Golub7, Nadia R. Roan8, Audrey L. French9, Michael H. Augenbraun3*, and Mark K. Slifka1*
1Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University 505 NW 185th Avenue, Beaverton, OR 97006, USA
2Biostatistics Shared Resource, Knight Cancer Institute, Biostatistics & Bioinformatics Core, Oregon National Primate Research Center, Oregon Health & Science University 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA 3Division of Infectious Diseases, Department of Medicine, SUNY Downstate Medical Center 450 Clarkson Avenue, Brooklyn, NY 11203, USA 4Department of Medicine, Georgetown University Medical Center 37th and O Streets, N.W., Washington D.C. 20057 5Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College of Cornell University 525 East 68th Street, New York, NY 10021 6Department of Pediatrics, Keck School of Medicine of USC 1975 Zonal Avenue, Los Angeles, CA 90033 7Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health 615 North Wolfe Street, Baltimore, MD 21205
Abstract
Background. It is unclear if HIV infection results in permanent loss of T cell memory or if it impacts pre-existing antibodies to childhood vaccinations/infections.
Methods. We conducted a matched cohort study involving 50 pairs of HIV+ and HIV- women. Total memory T cell responses were measured after anti-CD3 stimulation or after vaccinia virus stimulation to measure T cells elicited after childhood smallpox vaccination. Vaccinia-specific antibodies were measured by ELISA.
Results. There was no difference between HIV+ and HIV- subjects in terms of CD4+ T cell responses after anti-CD3 stimulation (P=0.19) although HIV+ subjects had significantly higher CD8+ T cell responses (P=0.033). In contrast, there was a significant loss in vaccinia-specific CD4+ T cell memory among HIV+ subjects (P=0.039) whereas antiviral CD8+ T cell memory remained intact (P=1.0). Vaccinia-specific antibodies were maintained indefinitely among HIV- subjects (half-life; infinity, 95%CI, 309 years-infinity) but declined rapidly among HIV+ subjects (half-life; 39 years, 95%CI, 24-108 years, P=0.001).
Conclusions. Despite ART-associated improvement in CD4+ T cell counts (nadir CD4 <200 cells/mm3 with >350 cells/mm3 after ART), antigen-specific CD4+ T cell memory to vaccinations/infections that occurred before HIV infection did not recover after immune reconstitution and a previously unrealized decline in pre-existing antibody responses was observed.
Background
Suppression of HIV replication using active antiretroviral therapies (ART) has allowed for restoration of immune function and many opportunistic infections, once common are now rare[1]. Despite these advancements, HIV+ individuals continue to suffer from a 4-fold greater incidence of varicella zoster[2] and other virus-associated ailments[3], leading to the possibility that immune function may still not be fully optimal. Although ART improves many aspects of immunological function[4], there is continuing debate regarding the ability of ART to restore T cell memory to vaccines or infections that were encountered prior to HIV infection. Some studies indicate that pre-existing antigen-specific T cell memory is either lost[5-7] or restored[5, 8-10] after ART-associated immunereconstitution. Furthermore, little is known about the durability of pre-existing serum antibody responses after HIV/ART[11, 12]. Since HIV+ individuals often demonstrate immunological characteristics that are more commonly associated with an aging immune system[13], this raises questions regarding whether HIV infection exacerbates immune senescence in part by decreasing protective immunological memory to vaccinations or infections that occurred in the distant past. Vaccinia virus (used during smallpox vaccination) represents an ideal antigen for determining the duration of immunity in the absence of re-infection since, a) the last case of smallpox in the U.S. occurred in 1949[14, 15], b) routine civilian smallpox vaccination was discontinued in 1972[16], and c) there are no cross-reactive orthopoxviruses in the U.S. that commonly infect humans. Moreover, vaccinia has the added advantage of inducing strong antiviral CD4+ and CD8+ T cell memory and readily infects primary monocytes[17], an antigen presenting cell (APC) found among peripheral blood mononuclear cells (PBMC) that can present virus-specific peptides to both CD4+ and CD8+ T cells and thus allows direct quantitation of virus-specific memory T cells. Here, we measured immune responses after smallpox vaccination as a well-characterized and robust model to determine the persistence of virus-specific T cell memory and antibody responses following childhood vaccination among HIV- and HIV+ women who underwent successful immune reconstitution after antiretroviral therapy.
Conclusions
We examined the durability of antiviral T cell and antibody responses following childhood smallpox vaccination as a model to determine the impact of HIV and ART on the maintenance of pre-existing immunological memory in the absence of re-exposure or revaccination. After ART-associated immune reconstitution, HIV+ women showed no reduction in the percentage of functional, anti-CD3-responsive CD4+ T cells. However, when antigen-specific assays were employed to study immunity from smallpox vaccination, we found a nearly complete loss of virus-specific CD4+ T cell memory even though CD8+ T cell responses remained largely unchanged in comparison to HIV- controls. Analysis of vaccinia-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 prior to HIV acquisition could have implications with regard to protective immunity to common acute or chronic viral infections.
CD44+ T cell-meddiated cytokine responses after polyclonal anti-CD3 stimulation was not significantly different between HIV+ women or HIV- controls (P = 0.19, Fig. 1). In contrast, anti-CD3-responsive CD8+ T cell responses were significantly upregulated among the HIV+ cohort (P = 0.033). These results are consistent with prior studies in which polyclonal stimulation of peripheral T cells from HIV+ subjects showed that CD4+ T cell responses were equal to or lower than HIV- controls whereas CD8+ T cell responses were consistently higher among HIV+ cohorts[32-34]. Although the reason for increased CD8+ T cell responses among HIV+ subjects 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, vaccinia virus-specific memory CD8+ T cell responses observed among HIV+ women appeared to be similar to that observed among HIV- women in terms of the overall magnitude of the remaining memory T cell response per subject (Fig. 2C) and in terms of the proportion of subjects who maintained a detectable CD8+ memory T cell response (Fig. 2D). One challenge with interpreting these studies is the low frequency of T cell memory identified at late time points examined decades after acute vaccinia infection[19] and more studies are needed in order to determine if the persistent inflammation and "inflammaging" phenotype observed among HIV+ subjects might contribute to a more stable frequency of pre-existing CD8+ memory T cells or if the increased frequency of CD8+ T cells with a functional memory phenotype (Fig. 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 re-exposure after ART (e.g., cytomegalovirus, herpes simplex virus, Candida albicans, etc.)[5, 8, 9]. In one study, lymphoproliferative responses to tetanus toxoid were restored regardless of booster immunization[10]. In another study[9], lymphoproliferative responses to PPD, influenza, and tetanus toxoid remained persistently weak even after ART. CD4 nadir before ART may influence immune reconstitution since vaccine-induced CD4+ T cell memory did not recover among HIV+ subjects with a low CD4 nadir of ≤350/mm3 whereas subjects with CD4 counts remaining above 350/mm3 had memory CD4+ T cell responses that remained intact[6]. In our studies, we examined the recall responses to vaccinia virus antigens that are unlikely to be encountered after cessation of routine smallpox vaccination among civilians born after 1972. We enrolled HIV+ subjects who had CD4 nadir <200/mm3 that rebounded to >350/mm3 after ART and found that CD4+ T cell memory was lost among HIV+ subjects whereas antiviral CD8+ T cell memory remained intact (Fig. 2). Since 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 instead indicates 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+ individuals have been well-described[28, 35, 36]. Much less is known about the impact of HIV/ART on the maintenance of pre-existing humoral immunity. In one study, antibody responses to tetanus were maintained among 7 HIV+ subjects on ART with an average 11 year half-life[11], similar to previous studies of 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+ population as observed in our study (Fig. 3). Alternatively, the antibody decay rates could be different for particular virus or vaccine antigens. One study observed a non-significant trend towards more rapid measles antibody decay rates during primary HIV infection[12] but when monitored longitudinally during the chronic phase of infection, the antibody responses appeared 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 if rapid loss of serological memory among HIV+ subjects is unique to specific viruses/vaccine antigens or if it represents a more global defect in immune memory among these individuals. For instance, the overall rate of herpes zoster from varicella zoster virus (VZV) among HIV+ 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 HAART, the incidence of certain virus-associated cancers such KS and NHL decreased whereas cervical cancer incidence 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 pre-existing serological memory among HIV+ subjects 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/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 gp120 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 the two may lead to disruption of the bone marrow microenvironment needed to sustain plasma cell survival and long-term antibody responses.
This study has several limitations. We examined immunological memory among HIV+ individuals who had CD4 nadir of <200 cells/mm3 that reconstituted to >350 cells/mm3 following ART. While these levels seem adequate to describe a population experiencing severe immunologic damage and significant recovery, additional studies will be needed to determine if those with higher nadir or those with greater recovery (i.e. >500/mm3) are likely to demonstrate loss of CD4+ T cell memory (Fig. 2) or rapid decline in pre-existing antibody responses (Fig. 3). As with any long-term cohort study, a proportion of subjects are lost to follow-up due to death or attrition and it is unknown if this may impact study results. In addition, this initial study focused on HIV+ women and further studies among HIV+ men are warranted.
Despite effective immune reconstitution with ART, the loss of immunological memory to prior infections/vaccinations may play a previously overlooked role in chronic inflammation and "accelerated aging" observed among HIV+ 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+ people at increased risk for virus-associated disease manifestations
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