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Poor maintenance of immunological memory to antigens previously encountered in life through natural infection or vaccination has been a focus of many previous studies in persons with human immunodeficiency virus (PWH). Whether administration of antiretroviral therapy (ART) reinvigorates previously established immunological memory to vaccines by controlling human immunodeficiency virus (HIV) replication and severe inflammation in PWH remains debatable. It is important to discern whether memory immune responses against a previous microbial vaccine are rejuvenated within the patient’s immune system or elicited ex novo by a pathogen circulating in the environment. In this issue of the Journal of Infectious Diseases, Archana et al [1] elegantly circumvented this complex problem by studying T-cell and serological memory to vaccinia virus that was used for vaccination against smallpox virus; the last case of infection with smallpox was reported in the United States in 1949 [2], and vaccination with vaccinia virus was discontinued in 1972 [3]. Persistent immunological memory to smallpox in the cohort included in the present study cannot be due to smallpox virus circulation in society, because the analyses were conducted in HIV-positive women born before 1971 and previously vaccinated with vaccinia virus and an age-matched group of HIV-negative women. The CD4+ T-cell count in patients increased from <200 to >350 cells/mm3 after ART administration.
The study revealed a dichotomy in maintenance of vaccinia-specific memory CD4+ and CD8+ T-cell responses in HIV-infected women [1]. Vaccinia-specific CD4+ T-cell responses, including both the number of specific memory CD4+ T cells but also the frequency of individuals showing detectable CD4+ T-cell responses, were consistently lower in PWH compared with control group. On the contrary, the percentage of HIV-infected and control individuals who maintained vaccinia CD8+ T-cell memory was comparable. These findings can be explained taking into consideration an altered T-cell homeostasis during HIV infection. Loss of antigen-specific memory CD4+ T cells are part of the dramatic CD4+ T-cell depletion caused directly by HIV and indirectly by bystander damage mechanisms. CD8+ T cells have another fate, as elevated blood CD8+ T-cell counts are found in HIV-infected patients [4]; CD8+ T-cell expansion includes the entire CD8+ T-cell population, with a broad range of antigen specificities [5]. Therefore, dynamics of CD4+ T-cell depletion and abnormal expansion of CD8+ T cells are likely to be reflected in loss or maintenance of vaccine-specific memory CD4+ and CD8+ T cells [1].
Initiation of ART during the early asymptomatic stage of HIV infection, defined by a CD4+ T-cell count of more than 500 cells/mm3, provides clinical and immunological benefits [6–8], and World Health Organization guidelines from 2015 support initiation of ART at HIV seroconversion. It would be relevant to know whether ART initiation at primary infection, when CD4+ T-cell loss is still confined, would lead to better preservation of vaccinia-specific CD4+ and CD8+ T-cell responses in patients born when the smallpox vaccination program was still active.
Vaccinia-specific antibody responses were maintained in the control group with an estimated half-life of infinity, whereas in the HIV-infected group the estimated half-life was 39 years [1]. Among HIV-infected individuals, a rapid decline of antibody (Ab) titers was found in 20%. Loss of pre-existing immunological memory and poor Ab responses upon vaccination were previously reported in HIV-infected individuals [9, 10]. Of interest, in the results presented by Archana et al [1], a correlation was not found between loss of vaccinia-specific CD4+ T cells with the rapid decay of vaccinia-specific Abs in HIV-infected patients. This observation deserves attention because it may shed light on yet poorly characterized aspects of HIV immunopathology.
A key feature of primary adaptive immune responses is the rapid production of high-affinity Abs generated through antigen activation and proliferation of naive B cells in secondary lymphoid organs, either as result of the germinal center (GC) reaction or as an extrafollicular B-cell response. Within the GC reaction, antigen-specific B cells receive signals from follicular T helper cells (TFH) leading to affinity maturation, class switch, and differentiation into either memory B cells (MBCs) or Ab-secreting cells (ASCs). Eventually, MBCs and ASCs exit the lymph node; MBCs enter the circulation [11, 12] where they can be detected for many years [13], whereas the presence of ASCs in blood is only transient (days or weeks) as most ASCs migrate to bone marrow (BM) for further maturation [14]. Only a small fraction of ASCs further differentiates into long-lived plasma cells (LLPCs), whereas the remaining undergo apoptosis. Long-term serological memory is dependent on continuous Ab production from LLPCs residing in BM.
Long-lived plasma cells reside in close contact with BM mesenchymal stromal cells (BMSCs) and with a wide range of other cell types including megakaryocytes, neutrophils, and antigen-presenting cells. (Figure 1A) CXCL12, interleukin-6 (IL-6), BAFF, and APRIL cytokines secreted from BMSCs provide homing and survival signals for ASCs, helping them to reach the BM niche; the APRIL/BAFF signaling pathway is also important for ASC maturation to LLPCs in BM [12]. Although both LLPCs and BMSCs express the HIV coreceptors CXCR4 and CCR5, neither cell type is susceptible to HIV infection [15]. However, several HIV proteins (gp120, Gag, Tat, and Rev) directly bind to BMSCs, a process shown in vitro to affect differentiation and biology of BMSCs [16]. Yuan et al [17] incubated human BMSCs with HIV-1 p55 gag-protein in vitro for 20 days followed by measurement of factors characteristic of BM niches. It is interesting to note that p55-Gag induced senescence of BMSCs with reduced IL-6 secretion and declined expression of several hematopoietic growth factors. Taking advantage of the simian immunodeficiency virus (SIV) rhesus macaque model, the role of BM niche factors for LLPC biology has also been studied in vivo. Shaw et al [18] studied low and high viremic SIV-infected macaques to elucidate the transition of ASC to LLPCs in BM niches during SIV infection. The data showed a positive correlation between the number of ASCs and plasma cells in BM niches, emphasizing the common lineage of these 2 cell types. Surprisingly, the ASC number negatively correlated with viral load and plasma cells also demonstrated a trend toward an inverse correlation with viral load [18]. These findings indicate that (1) during highly viremic SIV infection fewer ASCs reach the BM niche, thus impacting on the number of LLPC generated within this organ, and (2) an efficient primary antigen-specific B-cell response is important to generate a number of ASCs sufficient to ensure maintenance of a consistent pool of antigen-specific LLPCs. Taken together, data from both human and animal studies suggest that HIV infection imposes damage to the biology of BM niches and alters the production of molecules important for maintenance of BM LLPCs. Damage induced to the BMSCs by HIV viremia may affect, in a T cell-independent matter, the survival of vaccinia-specific LLPCs within their niches (Figure 1B), a process that likely involves LLPCs of several specificities and which may be difficult to correct when ART is initiated during the chronic phase of infection.
Cytokines produced from stromal cells in the bone marrow (BM) contribute to survival of long-lived plasma cells (LLPCs) within BM niches (A). Stromal cells express the human immunodeficiency virus (HIV) coreceptors CCR5 and CXCR4 and can bind HIV proteins; the binding of HIV proteins to HIV coreceptors leads to impaired production of cytokines important for LLPCs survival and reduced number of LLPCs within the BM niches (B). Other cells contributing to the biology of the niches, including megakaryocytes, neutrophils, and antigen-presenting cells, are shown in gray because their role was not presented in detail.
When serological memory mediated by circulating Abs is breached, the existing pool of MBCs will, upon antigen encounter, undergo additional expansion, affinity maturation, and differentiation in GCs and ultimately replenish the pool of LLPCs [19]. There are still several unresolved questions regarding maintenance and reactivation of MBCs including how antigen is captured and displayed for MBCs upon reactivation and if T-cell help is needed in this context. Depending on antigen specificity and immunoglobulin class, there are probably many different MBC niches, as opposed to the well described LLPC niche in BM. One relevant aspect of HIV pathogenesis is that the frequency of classic MBCs is significantly reduced in blood [9, 20], likely preventing replenishing of BM LLPCs when the level of vaccine-specific Abs is reduced in the circulation. For pathogens that no longer circulate in the environment, eg, smallpox virus, MBCs will have no impact on replenishment of the BM LLPCs pool; however, it was shown that loss of MBCs in HIV infection will have a direct impact on serological memory to childhood vaccines, possibly preventing replenishment of LLPC niches [20, 21], an immunopathological process that can be confined by early ART administration to HIV-infected children, leading to MBCs pool preservation [21].
Archana et al [1] discuss whether rapid loss of serological memory is unique to specific viruses/antigens or if it represents a global loss of Abs. The latter hypothesis is substantiated by one study examining Abs to live-attenuated vaccines (measles, mumps, rubella) compared with Abs generated during wild-type infection (varicella-zoster virus, cytomegalovirus, Epstein-Barr virus [EBV]); the results showed that Abs to both types of antigens disappeared over time with the exception of Abs to EBV [22]. Special attention, in this context, should be given to HIV-infected pregnant women, because Abs passing the placental barrier between mother and child play a pivotal role for protection from microbes during early life. That HIV may represent a major problem in this context is shown by (1) reduced Ab levels to measles and other vaccination antigens in HIV-infected and HIV-exposed noninfected children born to HIV-infected mothers and (2) the inadequate response of these children to vaccines provided during childhood [23, 24].
Notes
Financial support. This work funded by grants from the Swedish Medical Research Council (2017-02001 [to A. N.] and 2016-01165 [to F. C.]) and the Swedish Childhood Cancer Fund (2014-0112; to A. N.).
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
