Production of IgG2 Antibodies to Pneumococcal Polysaccharides After Vaccination of Treated HIV Patients May Be Augmented by IL-7Rα Signaling in ICOS+ Circulating T Follicular-Helper Cells

Greater understanding of factors influencing the maturation of antibody responses against pneumococcal polysaccharides (PcPs) may improve pneumococcal vaccination strategies. Although PcPs are type 2 T cell-independent antigens thought not to induce follicular immune responses, we have previously shown that IgG2 antibody responses against antigens in the 23-valent unconjugated PcP vaccine (PPV23) are associated with expansion of ICOS+ circulating T follicular helper (cTFH) cells in HIV seronegative subjects but not HIV patients. As IL-7Rα signaling in CD4+ T cells may affect TFH cell function and is adversely affected by HIV-1 infection, we have examined the relationship of IL-7Rα expression on ICOS+ cTFH cells with PcP-specific IgG2 antibody responses. PPV23 vaccination was undertaken in HIV patients receiving antiretroviral therapy (n = 25) and HIV seronegative subjects (n = 20). IL-7Rα expression on ICOS+ and ICOS− cTFH cells was assessed at day(D) 0, 7, and 28. Fold increase between D0 and D28 in serum IgG1 and IgG2 antibodies to PcP serotypes 4, 6B, 9V, and 14 and the frequency of IgG1+ and IgG2+ antibody secreting cells (ASCs) at D7 were also assessed. Decline in IL-7Rα expression on ICOS+ cTFH cells between D0 and D7 occurred in 75% of HIV seronegative subjects and 60% of HIV patients (Group A), with changes in IL-7Rα expression being more pronounced in HIV patients. Group A patients exhibited abnormally high IL-7Rα expression pre-vaccination, an association of serum IgG2, but not IgG1, antibody responses with a decline of IL-7Rα expression on ICOS+ cTFH cells between D0 and D7, and an association of higher IgG2+ ASCs with lower IL-7Rα expression on ICOS+ cTFH cells at D7. As decline of IL-7Rα expression on CD4+ T cells is an indicator of IL-7Rα signaling, our findings suggest that utilization of IL-7 by cTFH cells affects production of IgG2 antibodies to PPV23 antigens in some HIV patients

Isotype Diversification of IgG Antibodies to HIV Gag Proteins as a Therapeutic Vaccination Strategy for HIV Infection

The development of vaccines to treat and prevent human immunodeficiency virus (HIV) infection has been hampered by an incomplete understanding of “protective” immune responses against HIV. Natural control of HIV-1 infection is associated with T-cell responses against HIV-1 Gag proteins, particularly CD8+ T-cell responses restricted by “protective” HLA-B alleles, but other immune responses also contribute to immune control. These immune responses appear to include IgG antibodies to HIV-1 Gag proteins, interferon-a-dependant natural killer (NK) cell responses and plasmacytoid dendritic cell (pDC) responses. Here, it is proposed that isotype diversification of IgG antibodies against HIV-1 Gag proteins, to include IgG2, as well as IgG3 and IgG1 antibodies, will broaden the function of the antibody response and facilitate accessory cell responses against HIV-1 by NK cells and pDCs. We suggest that this should be investigated as a vaccination strategy for HIV-1 infection

Antiviral Functions of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific IgG Antibodies: Effects of Antiretroviral Therapy and Implications for Therapeutic HIV-1 Vaccine Design

Contemporary antiretroviral therapy (ART) is effective and tolerable for long periods of time but cannot eradicate human immunodeficiency virus type 1 (HIV-1) infection by either elimination of viral reservoirs or enhancement of HIV-1-specific immune responses. Boosting “protective” HIV-1-specific immune responses by active or passive immunization will therefore be necessary to control or eradicate HIV-1 infection and is currently the topic of intense investigation. Recently reported studies conducted in HIV patients and non-human primate (NHP) models of HIV-1 infection suggest that HIV-1-specific IgG antibody responses may contribute to the control of HIV-1 infection. However, production of IgG antibodies with virus neutralizing activity by vaccination remains problematic and while vaccine-induced natural killer cell-activating IgG antibodies have been shown to prevent the acquisition of HIV-1 infection, they may not be sufficient to control or eradicate established HIV-1 infection. It is, therefore, important to consider other functional characteristics of IgG antibody responses. IgG antibodies to viruses also mediate opsonophagocytic antibody responses against virions and capsids that enhance the function of phagocytic cells playing critical roles in antiviral immune responses, particularly conventional dendritic cells and plasmacytoid dendritic cells. Emerging evidence suggests that these antibody functions might contribute to the control of HIV-1 infection. In addition, IgG antibodies contribute to the intracellular degradation of viruses via binding to the cytosolic fragment crystallizable (Fc) receptor tripartite motif containing-21 (TRIM21). The functional activity of an IgG antibody response is influenced by the IgG subclass content, which affects binding to antigens and to Fcγ receptors on phagocytic cells and to TRIM21. The IgG subclass content and avidity of IgG antibodies is determined by germinal center (GC) reactions in follicles of lymphoid tissue. As HIV-1 infects cells in GCs and induces GC dysfunction, which may persist during ART, strategies for boosting HIV-1-specific IgG antibody responses should include early commencement of ART and possibly the use of particular antiretroviral drugs to optimize drug levels in lymphoid follicles. Finally, enhancing particular functions of HIV-1-specific IgG antibody responses by using adjuvants or cytokines to modulate the IgG subclass content of the antibody response might be investigated in NHP models of HIV-1 infection and during trials of therapeutic vaccines in HIV patients

Proportions of ICOS⁺ and ICOS^- cmT_FH cells pre- and post- vaccination in HIV patients and HIV seronegative subjects.

<p><b>(A)</b> ICOS⁺ cmT_FH cells, <b>(B)</b> ICOS^- cmT_FH cells. Data are presented on a log scale and were analysed by Mann-Whitney tests. n.s., not significant and p<0.05 considered significant, <b>(C)</b> Following vaccination with PcPs, ICOS⁺ cmT_FH cells increased at D7, compared with D0, in HIV seronegative subjects but not in ART-naive HIV patients and to a lesser and more variable degree in ART-treated patients and <b>(D</b>) ICOS^- cmT_FH cells did not increase in any of the study groups. Data were analysed by Wilcoxon signed-rank test and Kruskal Wallis test. n.s., not significant and p<0.05 considered significant.</p

Production of IgG antibodies to pneumococcal polysaccharides is associated with expansion of ICOS⁺ circulating memory T follicular-helper cells which is impaired by HIV infection

<div><p>Dysfunction of T follicular-helper (T_FH) cells is a possible cause of impaired germinal centre (GC) and IgG antibody responses in individuals with human immunodeficiency virus-1 (HIV-1) infection and might contribute to decreased magnitude and isotype diversification of IgG antibodies to pneumococcal polysaccharides (PcPs). We examined the production of IgG1 and IgG2 antibodies to PcPs 4, 6B, 9V and 14 by enumerating antibody secreting cells (ASCs) at day (D) 7 and determining fold-increase in serum antibody levels at D28 after vaccination with unconjugated PcPs in HIV seronegative subjects (n = 20) and in HIV patients who were receiving antiretroviral therapy (ART) (n = 28) or who were ART-naive (n = 11) and determined their association with ICOS⁺ and ICOS^- circulating memory T_FH (cmT_FH) cells (CD4⁺CD45RA^-CD27⁺CXCR5⁺PD-1⁺) and short lived plasmablasts (SPBs) at D7, and with PcP-specific and total IgM⁺ and IgG⁺ memory B cells at D0. In HIV seronegative subjects, production of IgG1⁺ and IgG2⁺ ASCs was consistently associated with the frequency of ICOS⁺ cmT_FH cells but not ICOS^- cmT_FH cells or memory B cells. In contrast, post-vaccination ASCs in HIV patients, regardless of ART status, were lower than in HIV seronegative subjects and not associated with ICOS⁺ cmT_FH cells, the expansion of which was absent (ART-naive patients) or much lower than in HIV seronegative subjects (ART-treated patients). Production of SPBs was also lower in ART-naive patients. Fold-increase in IgG2 antibodies at D28 also correlated with ICOS⁺ cmT_FH cells at D7 in HIV seronegative subjects but not in HIV patients. These novel findings provide evidence that ICOS⁺ cmT_FH cells contribute to the regulation of PcP-specific IgG antibody responses, including isotype diversification, and that T_FH cell dysfunction may be a cause of impaired PcP-specific IgG antibody responses and increased susceptibility to pneumococcal disease in HIV patients.</p></div

Immune correlates of PcP 4-specific IgG1⁺ and IgG2⁺ ASCs after vaccination with PcPs in HIV patients and HIV seronegative subjects.

<p>Immune correlates of PcP 4-specific IgG1⁺ and IgG2⁺ ASCs after vaccination with PcPs in HIV patients and HIV seronegative subjects.</p

Circulating SPB in HIV patients and HIV seronegative subjects at day 7 post-vaccination with PcPs.

<p>(<b>A</b>) SPB (CD20^-CD27⁺⁺CD38⁺⁺) at D0, D7 and D28 in the 3 study groups. The increase in SPB between D0 and D7 is shown for (<b>B</b>) ART-treated patients (<b>C</b>) ART-naive patients and (<b>D</b>) HIV seronegative subjects. Data were analysed using linear mixed models. n.s., not significant and p<0.05 considered significant.</p

PcP-specific IgG1⁺ and IgG2⁺ ASCs correlated with ICOS⁺ cmT_FH cells in HIV seronegative subjects at D7 post-vaccination.

<p><b>(A)</b> IgG1⁺ ASC <b>(B)</b> IgG2⁺ ASC. Data were analysed using Spearman’s rank correlation test.</p

PcP-specific IgG1⁺ and IgG2⁺ ASCs in HIV patients and HIV seronegative subjects at day 7 post-vaccination with PcPs.

<p><b>(A)</b> IgG1⁺ ASC to PcP 4, 6B, 9V and 14 <b>(B)</b> IgG2⁺ ASC to PcP 4, 6B, 9V and 14. Data are presented as ASC/2x10⁵ PBMC. The horizontal lines indicate median values. Median values of IgG1⁺ ASC/2 x10⁵ PBMC in ART-treated, ART-naive and HIV seronegative subjects to PcP 4: 0.5, 0 and 6, respectively; PcP 6B: 2, 1 and 6, respectively; PcP 9V: 1, 1 and 6, respectively and PcP 14: 0, 2 and 7, respectively. Median values of IgG2⁺ ASC/ 2x10⁵ PBMC in ART-treated, ART-naive and HIV seronegative subjects to PcP 4: 6, 7 and 21, respectively; PcP 6B: 7, 7 and 22, respectively; PcP 9V: 6, 3 and 21, respectively and PcP 14: 3, 8 and 22, respectively. Differences between groups were tested using Mann-Whitney tests. n.s., not significant and p<0.05 considered significant.</p