Increased Frequency of Virus Shedding by Herpes Simplex Virus 2-Infected Guinea Pigs in the Absence of CD4⁺T Lymphocytes

Abstract

Reactivation of herpes simplex virus 2 (HSV-2) results in infection of epithelial cells at the neuro-epithelial junction and shedding of virus at the epithelial surface. Virus shedding can occur in either the presence or absence of clinical disease and is usually of short duration, although the shedding frequency varies among individuals. The basis for host control of virus shedding is not well understood, although adaptive immune mechanisms are thought to play a central role. To determine the importance of CD4+ T cells in control of HSV-2 shedding, this subset of immune cells was depleted from HSV-2-infected guinea pigs by injection of an anti-CD4 monoclonal antibody (MAb). Guinea pigs were treated with the depleting MAb after establishment of a latent infection, and vaginal swabs were taken daily to monitor shedding by quantitative PCR. The cumulative number of HSV-2 shedding days and the mean number of days virus was shed were significantly increased in CD4-depleted compared to control-treated animals. However, there was no difference in the incidence of recurrent disease between the two treatment groups. Serum antibody levels and the number of HSV-specific antibody-secreting cells in secondary lymphoid tissues were unaffected by depletion of CD4+ T cells; however, the frequency of functional HSV-specific, CD8+ gamma interferon-secreting cells was significantly decreased. Together, these results demonstrate an important role for CD4+ T lymphocytes in control of virus shedding that may be mediated in part by maintenance of HSV-specific CD8+ T cell populations. These results have important implications for development of therapeutic vaccines designed to control HSV-2 shedding. IMPORTANCE Sexual transmission of HSV-2 results from viral shedding following reactivation from latency. The immune cell populations and mechanisms that control HSV-2 shedding are not well understood. This study examined the role of CD4+ T cells in control of virus shedding using a guinea pig model of genital HSV-2 infection that recapitulates the shedding of virus experienced by humans. We found that the frequency of virus-shedding episodes, but not the incidence of clinical disease, was increased by depletion of CD4+ T cells. The HSV-specific antibody response was not diminished, but frequency of functional HSV-reactive CD8+ T cells was significantly diminished by CD4 depletion. These results confirm the role of cell-mediated immunity and highlight the importance of CD4+ T cells in controlling HSV shedding, suggesting that therapeutic vaccines designed to reduce transmission by controlling HSV shedding should include specific enhancement of HSV-specific CD4+ T cell responses.

Analysis of Lymphocyte T(CD4+) Cells Expression on Severe Early Childhood Caries and Free Caries

“…CD4 + lymphocyte cells are then activated and produce cytokines to start the immune response of leukocyte cells or other immune cells of cell-mediated immunity and activate humoral immunity branches that depend on T cells, then CD4 + T cells recognize protein antigens and activate B cells to produce immunoglobulins in response to antigens. 19 , 20 The results of the study as shown in Table 1 show that the expression of T lymphocytes (CD4 + ) cells in S-ECC is significantly lower than in free caries, this may cause the high S. mutans bacteria found in S-ECC saliva cannot be in acquisition by adaptive immunity because TCR and its co-receptors, such as CD4 which can form complexes with class 2 major receptor histocompatibility complex (MHC) receptors and antigens, cannot function optimally so that quantitatively the number of S. mutans which are bacteria that causes caries is higher compared to cariesfree children. 21 Expression of T lymphocytes (CD4 + ) in S-ECC causes the release of pro-inflammatory cytokines that function as chemoattractant of neutrophil cells, because the movement of neutrophils toward the infection area is less than optimal, the movement of macrophages is also less than optimal towards the area of infection, giving S. mutans the opportunity to develop and do damage to the teeth.…”

B cells, antibody-secreting cells, and virus-specific antibodies respond to herpes simplex virus 2 reactivation in skin

“…Whether anti-viral activity is related to systemic or local secretion of antibody is an area of active investigation. In a guinea pig HSV2 infection model where recurrences have been observed, ASCs have only been seen in secondary lymphoid and neuronal tissues (22,23), and systemically-infused antibody rescued control of HSV2 shedding in B-cell depleted animals (21). In HSV2-exposed mice, however, B cells (both CD20 + and CD138 + IgG + ) infiltrate into the vaginal mucosa in response to immunization and rechallenge with latency-deficient HSV2.…”

Alphaherpesvirus Latency and Reactivation with a Focus on Herpes Simplex Virus

“…However, immunosuppression of latently infected mice failed to induce reactivation or produce recurrent disease (Blyth et al, 1981;Hurd and Robinson, 1977;Stevens and Cook, 1973), with only a low incidence of recurrence in hairless mice treated with the immunosuppressant drug, prednisone, being observed (Underwood and Weed, 1974). Conflicting with these findings is the more recent hypothesis that CD8 T-cells directed against a specific epitope on glycoprotein B may play a role in the maintenance of HSV1 latency (Bourne et al, 2018;Held and Derfuss, 2011;Knickelbein et al, 2008;Lahmidi et al, 2017;Liu et al, 2000;Treat et al, 2017). In contrast to HSV, depletion of CD4 cells induced reactivation of simian varicella virus in Rhesus Macaques (Traina-Dorge et al, 2019).…”