Intrinsic immunogenicity is a major determinant of type-specific responses in SARS-CoV-2 infections.

To investigate whether there are differences in the virus-specific CD4 T cell response during primary HIV-1 infection in patients who naturally (without antiretroviral intervention) control viral replication with differing efficiencies. CD4 T cell responses to recombinant HIV proteins (Gag p24 and p55 and Env gp160) and an inactivated HIV-1 preparation were analysed using interferon-gamma ELISPOT assays (with CD8-depleted peripheral blood mononuclear cells) and by intracellular interferon-gamma staining and fluorescent-activated cell sorting. Strong HIV-specific CD4 T cell responses were detected from the earliest time-points analysed in primary infection in patients who naturally established low persisting viral loads. By contrast, HIV-specific CD4 T cell responses were weaker (at or just below the limit of detection in our assays) at similar time-points in patients who went on to establish high persisting viral loads. Statistical analysis revealed a highly significant difference (P < 0.001) between the magnitudes of the Gag p24-specific response at the earliest time-point analysed in primary infection in the two sets of patients. Strong HIV-specific CD4 T cell responses are associated with efficient natural control of primary HIV-1 infection.

BackgroundVery little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA) modulation of disease progression.Methods and FindingsIn a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8+ T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8+ T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8+ T cell response during primary infection.ConclusionsThese data demonstrate consistent immunodominance patterns of HIV-1-specific CD8+ T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression.

Herpes simplex virus type-specific antibody determination by enzyme-linked immunosorbent assay in human sera

Infection with multiple cytomegalovirus (CMV) strains (mixed infection) was reported in a variety of hosts. As the virus genetic diversity in primary CMV infection and the changes over time remain incompletely defined, we examined CMV diversity and changes in diversity over time in healthy adolescent females who participated in a phase 2 CMV gB/MF59 vaccine trial. CMV genetic diversity was determined by genotyping of 5 genes-gB (UL55), gH (UL75), gN (UL73), US28, and UL144-in urine, saliva, and plasma samples from 15 study subjects. At the time of primary infection, 5 of 12 (42%) urine samples had multiple virus strains, and 50% of vaccine recipients were infected with gB1 genotype (vaccine strain). Mixed infection was documented in all 15 subjects within 3 months after primary infection, and the majority had different CMV genotypes in different compartments. Changes in genotypes over time were observed in all subjects. Infection with multiple CMV genotypes was common during primary infection and further diversification occurred over time. Infection with gB1 genotype in vaccine recipients suggests a lack of strain-specific protection from the vaccine. As only 5 polymorphic genes were assessed, this study likely underestimated the true genetic diversity in primary CMV infection.

Cellular immune responses are of high importance in initiating and maintaining immunity against virus infections. Whereas the cellular immune response during persistent cytomegalovirus (CMV) infection is well assessable, the individual contribution of CD4 and CD8 T cell responses during primary infection has not been described. A novel whole-blood assay, which relies on the flow-cytometric detection of antigen-induced cytokine expression, was used to characterize CMV-specific CD4 and CD8 T cell responses during primary infection of CMV seronegative recipients of a renal allograft from a CMV seropositive donor. These T cell responses were compared with long-term CMV-positive patients with known history of transplantation-related seroconversion. Results were further correlated to CMV load and serum IgG and IgM. The long-term seroconverted patients consistently showed a dominant CMV-specific CD4 T cell response (median frequencies: CD4, 1.12% [range, 0.35 to 8.10%] versus CD8 0.13% [range, <0.05 to 0.55%]). In contrast, during primary infection, the cellular immune response is strongly dominated by CMV-specific CD8 T cells (median peak frequencies: CD4, 1.24% [range, 0.21 to 1.60%] versus CD8, 2.47% [range, 1.34 to 6.67%]). Upon receipt of ganciclovir, viral load as well as CMV-specific CD8 responses decreased. The frequency of the respective CD4 T cells fluctuated during decrease of CMV load and became dominant over CMV-specific CD8 T cell responses. These results are consistent with the view of an effective direct antiviral activity of CD8 T cells, which is most critical during periods of high viremia. Later on during persistent infection, CD4 T cells dominate the immune response to support the state of antiviral immunity.

An early marker of fetal infection after primary cytomegalo-virus infection in pregnancy

Multiple lines of evidence support a role for CD8(+) T cells in control of acute/early HIV replication; however, features of the primary HIV-specific CD8(+) T cell response that may impact on the efficiency of containment of early viral replication remain poorly defined. In this study, we performed a novel, comprehensive analysis of the kinetics of expansion of components of the HIV-specific CD8(+) T cell response in 21 acutely infected individuals. Epitope-specific T cell responses expanded asynchronously during primary infection in all subjects. The most rapidly expanded responses peaked as early as 5 days following symptomatic presentation and were typically of very limited epitope breadth. Responses of additional specificities expanded and contracted in subsequent waves, resulting in successive shifts in the epitope immunodominance hierarchy over time. Sequence variation and escape were temporally associated with the decline in magnitude of only a subset of T cell responses, suggesting that other factors such as Ag load and T cell exhaustion may play a role in driving the contraction of HIV-specific T cell responses. These observations document the preferential expansion of CD8(+) T cells recognizing a subset of epitopes during the viral burst in acute HIV-1 infection and suggest that the nature of the initial, very rapidly expanded T cell response may influence the efficiency with which viral replication is contained in acute/early HIV infection.

Induction of type-specific and cross-protective immune responses against human parainfluenza viruses have been investigated. The envelope glycoproteins HN (76 kDa) and F0 (62 kDa) from parainfluenza type 2 virus were selectively solubilized with octylglucoside. Detergent-soluble envelope glycoproteins were used as vaccine antigens for intranasal immunization of hamsters. The immunized animals showed complete protection from challenge infection with prototype live virus but failed to demonstrate a significant level of protection against either human parainfluenza type 1 or type 3 virus. The sera and bronchial lavages of immunized animals also showed type-specific neutralizing antibodies. A similar type-specific protective immune response was also noted after primary infection with live virus. The results indicate that a multivalent parainfluenza virus vaccine is probably required for protection against natural infection.

Infections with respiratory syncytial virus (RSV) occurs repeatedly throughout life because sustained, protective memory responses fail to develop. Why this occurs is not known. During RSV infection the recognition of the virus via the cytosolic RIG-I like receptors and signaling via the adaptor protein MAVS is crucial for mounting an innate immune response. However, if this signaling pathway is important for T cell responses during primary infection and during re-infection is not fully elucidated. We describe a second peak of pro-inflammatory mediators during the primary immune response to RSV that coincides with the arrival of T cells into the lung. This second peak of cytokines/chemokines is regulated differently than the early peak and is largely independent of signaling via MAVS. This was concurrent with Mavs−/− mice mounting a strong T cell response to primary RSV infection, with robust IFN-γ; and Granzyme B production. However, after RSV re-infection, Mavs−/− mice showed fewer CD4+ and CD8+ short term memory T cells and their capacity to produce IFN-γ; and Granzyme B, was decreased. In sum, cytosolic recognition of RSV is important not only for initiating innate anti-viral responses but also for generating or maintaining efficient, short term T cell memory responses.

Primary virus infection often elicits a large CD8+ T cell response which subsequently contracts to a smaller memory T cell pool; the relationship between these two virus-specific populations is not well understood. Here we follow the human CD8+ T cell response to Epstein-Barr virus (EBV) from its primary phase in infectious mononucleosis (IM) through to the persistent carrier state. Using HLA-A2.1 or B8 tetramers specific for four lytic cycle and three latent cycle epitopes, we find marked differences in the epitope-specific composition of the T cell populations between the two phases of infection. The primary response is dominated by lytic epitope specificities which are severely culled (and in one case extinguished) with resolution of the acute infection; in contrast latent epitope specificities are less abundant, if present at all, in acute IM but often then increase their percentage representation in the CD8 pool. Even comparing epitopes of the same type, the relative size of responses seen in primary infection does not necessarily correlate with that seen in the longer term. We also follow the evolution of phenotypic change in these populations and show that, from a uniform CD45RA−RO+CCR7− phenotype in IM, lytic epitope responses show greater reversion to a CD45RA+RO− phenotype whereas latent epitope responses remain CD45RA−RO+ with a greater tendency to acquire CCR7. Interestingly these phenotypic distinctions reflect the source of the epitope as lytic or latent, and not the extent to which the response has been amplified in vivo.

HIV-1 specific immune responses unequivocally play a major role in determining the natural history of HIV-1 infection. The decreases in viral load which occur during primary infection are several orders of magnitude greater than the decreases observed when antiretroviral chemotherapy is initiated. Delineation of the range of immune effector mechanisms responsible for the brick decrease in viral replication during primary HIV-1 infection is an active research topic of high priority. To date, attempts to manipulate HIV-1 specific immune responses in vivo have resulted in relatively modest changes in HIV-1 specific humoral or cellular immune responses that have not been associated with convincing changes in viral load or with cleancut clinical benefit. Further investigation of therapeutic interventions directed at manipulating HIV-1 specific immune responses is warranted, but the same paradigms that have evolved to assess efficacy of antiretrovirals should be applied to HIV-1 specific immunotherapeutics, when making decisions regarding the expansion of pilot (Phase I/II) studies to larger scale studies with clinical endpoints.

BALB/c mice were depleted of B cells by anti-mu treatment to investigate the pathogenesis of respiratory syncytial virus (RSV) infection in the absence of antibody. Termination of RSV replication after primary infection occurred with the same kinetics in anti-mu-treated mice as in phosphate-buffered saline (PBS)-treated controls. Yet, when rechallenged, anti-mu-treated mice were more permissive to RSV replication than PBS-treated controls. Anti-mu-treated mice also experienced greater illness than PBS-treated controls during both primary infection and rechallenge. Passive transfer of RSV-specific immune serum to anti-mu-treated mice before rechallenge reconstituted complete protection from RSV replication and diminished illness. Thus, RSV-specific antibody is not required to terminate RSV replication in primary infection, but without antibody, only partial immunity against rechallenge is induced. While it is unknown whether the mechanism is a direct effect on RSV titer or modulation of the illness-causing cellular immune response, the presence of RSV-specific antibody reduces illness in both primary RSV infection and rechallenge of mice.

A key component of immunity against viruses, CD4(+) T cells expand and differentiate into functional subsets upon primary infection, where effector (Teff) cells facilitate infection control and regulatory (Treg) cells mitigate immunopathology. After secondary infection, Teff cells mount a robust response from the memory pool. Here, we show that Treg-cell responses are diminished upon secondary infection, and Treg-cell response dynamics are associated more with T-cell receptors (TCRs) repertoire and avidity than with epitope specificity. In the murine model, the IA(b) M209 epitope of respiratory syncytial virus is recognized by both CD4(+) Treg and Teff cells, while the IA(b) M226 epitope is recognized almost exclusively by CD4(+) Teff cells expressing high avidity TCR Vβ8.1/8.2 and dominating the CD4(+) T-cell response during primary and secondary infections. IA(b) M209 -Teff cells express relatively low avidity TCRs during early primary infection, but high avidity TCR Vβ7-expressing IA(b) M209 -Teff cells emerge during the late phase, and become dominant after secondary infection. The emerging high avidity IA(b) M209 -Teff cells outcompete IA(b) M209 -Treg cells that share the same epitope, but have low avidity and are restricted to TCR Vβ2 and Vβ6 subpopulations. These data indicate that MHC-peptide-TCR interactions can produce different kinetic and functional profiles in CD4(+) T-cell populations even when responding to the same epitope.

Immune responses to an attenuated West Nile virus NS4B-P38G mutant strain

Age-associated decreases in the CD8+ T cell primary and secondary responses of mice to influenza A virus infection were examined by comparing young (2 months) and aged (22–24 months) C57BL/6 mice. A significant age-associated decrease was seen in both the percentage and number of virus-specific CD8+ T cells following both primary and secondary infection. In both age groups there was a strong correlation between influenza peptide-specific tetramer+ and IFNg+ cells. Clearance of virus from the lungs, following primary infection corresponded with the time point at which maximal levels of both percentages and numbers of virus-specific CD8+ T cells were seen for both age groups. There was a delay in the maximal expansion of virus-specific CD8+ T cells in the aged mice compared to young mice following primary infection and a corresponding delay in viral clearance. A significant age-associated decrease in the cytotoxic activity was seen. Cytotoxic activity was closely correlated with the numbers of virus-specific CD8+ T cells suggesting that the age-associated problems with CD8+ T cell activity against influenza are due to decreased numbers of cells able to respond initially or a defect in expansion of these cells once exposed to the virus, rather than effector activity on a per cell basis. This was further supported by the fact that following thymic regeneration, caused by castration, there was an increase in the numbers of naïve T cells in the periphery of aged-mice with a consequent increase in the numbers of virus-specific cells and an increased ability to clear virus.