Anne Hosmalin

Type I Interferon Production Is Profoundly and Transiently Impaired in Primary HIV-1 Infection

BACKGROUNDnSuccessful immunological control of human immunodeficiency virus (HIV) infection is achieved only in rare individuals. Plasmacytoid dendritic cells (DCs) are mostly responsible for the production of strong antiviral factors--that is, type I interferons (IFNs)--in response to viruses. Their natural IFN production is impaired in chronic HIV infection, in correlation with viral load and disease progression, but it has not been tested during the critical stage of primary infection, when a balance is set between host immune responses and viral replication.nnnMETHODSnWe longitudinally studied 26 patients during the primary stage of HIV infection. Fifteen patients received highly active antiretroviral therapy (HAART) for 12 months.nnnRESULTSnAt the time of inclusion into the cohort, median type I IFN production in response to herpes simplex virus type 1 stimulation was dramatically impaired in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients, compared with that in PBMCs from 31 uninfected donors (180 vs. 800 IU/mL; P<.0001). Median circulating plasmacytoid DC counts were also significantly decreased (7300 vs. 13,500 cells/mL; P=.001). Twelve months later, IFN production returned to normal, and the data suggest that HAART may help in the recovery of IFN production by plasmacytoid DCs.nnnCONCLUSIONSnThese data underline the potential for early antiretroviral treatment and IFN- alpha treatment to enhance viral control in a larger proportion of patients during the critical stage of primary infection.

Monocyte-derived dendritic cells have a phenotype comparable to that of dermal dendritic cells and display ultrastructural granules distinct from Birbeck granules.

Most monocyte‐derived dendritic cells (DC) display CD1a, like Langerhans cells (LC) and some dermal DC, but their relationship with these skin DC remains unclear. To address this issue, we studied the expression of different antigens characteristic of skin DC and of monocyte/macrophages in CD1a+ and CD1a– monocyte‐derived DC. Their phenotype indicated that they may be related to dermal DC rather than to LC, i.e., they were all CD11b‐positive, and 72% were Factor XIIIa‐positive, but they did not express E‐cadherin nor VLA‐6. It is interesting that CD1a+ and CD1a– cells showed intracytoplasmic granules that were different from LC Birbeck granules. These pheno‐typical and ultrastructural features are comparable to those of CD14‐derived DC obtained from cord blood precursors [C. Caux et al. J. Exp. Med. 184, 695–706]. These results show a close relationship between these two in vitro models, which are both related to dermal DC. J. Leukoc. Biol. 64: 484–493; 1998.

Cytotoxic T-cell responses to HIV-1 reverse transcriptase, integrase and protease.

Objectives:To determine immunodominant regions and new epitopes for cytotoxic T cells (CTL) directed against the HIV-1 pol products reverse transcriptase (RT), integrase and protease in a large cohort of patients at different stages of disease. Design and methods:Cross-sectional analysis of 98 patients from the French IMMUNOCO cohort (CD4 counts: 125–1050 × 106 cells/l), monitored for CTL recognition of HIV-1 pol products using recombinant vaccinia virus constructs and synthetic peptides. Results:Memory CTL responses against HIV-1 pol products were detected in 78% of all patients whatever the stage of disease. RT was more immunogenic (81%, 30 out of 37 patients) than integrase and protease (51% and 24%, respectively). CTL recognition of RT was more frequent against Pol amino acids 310–460 (61%, 11 out of 18 patients) than against the other three portions (Pol 168–310, Pol 450–600, Pol 590–728) in patients with CD4 counts > 400 × 106/l, whereas in patients at advanced stages no prominent differences were observed. Two new clusters of antigenic regions were found in the NH2 segment: three epitopes between amino-acids Pol 200 and 217 and four epitopes between amino-acids Pol 346 and 387, using five different HLA-restricting elements. A new cluster of three conserved epitopes was found in the COOH segment of RT. Conclusions:This study shows that memory CTL responses against HIV-1 RT, integrase and protease are detectable in most patients at different stages of disease. The capacity of CTL to recognize simultaneously clusters of epitopes may become important for the immune control to reinforce antiretroviral drug efficiency.

HIV-Infected Spleens Present Altered Follicular Helper T Cell (Tfh) Subsets and Skewed B Cell Maturation

Follicular helper T (Tfh) cells within secondary lymphoid organs control multiple steps of B cell maturation and antibody (Ab) production. HIV-1 infection is associated with an altered B cell differentiation and Tfh isolated from lymph nodes of HIV-infected (HIV+) individuals provide inadequate B cell help in vitro. However, the mechanisms underlying this impairment of Tfh function are not fully defined. Using a unique collection of splenocytes, we compared the frequency, phenotype and transcriptome of Tfh subsets in spleens from HIV negative (HIV-) and HIV+ subjects. We observed an increase of CXCR5+PD-1highCD57-Tfh and germinal center (GC) CD57+ Tfh in HIV+ spleens. Both subsets showed a reduced mRNA expression of the transcription factor STAT-3, co-stimulatory, regulatory and signal transduction molecules as compared to HIV- spleens. Similarly, Foxp3 expressing follicular regulatory T (Tfr) cells were increased, suggesting sustained GC reactions in chronically HIV+ spleens. As a consequence, GC B cell populations were expanded, however, complete maturation into memory B cells was reduced in HIV+ spleens where we evidenced a compromised production of B cell-activating cytokines such as IL-4 and IL-10. Collectively our data indicate that, although Tfh proliferation and GC reactions seem to be ongoing in HIV-infected spleens, Tfh “differentiation” and expression of costimulatory molecules is skewed with a profound effect on B cell maturation.

Dynamics of HIV variants and specific cytotoxic T-cell recognition in nonprogressors and progressors

Infection with the human immunodeficiency virus (HIV) results in a disease characterized by a rapid viral replication, immunodeficiency and chronic immune activation. The vigorous polyspecific cytotoxic T-cell (CTL) response directed against multiple HIV epitopes reduces HIV-infected cell numbers, although unable to eradicate the virus. The plasticity of the specific CTL repertoire ensures adaptation to the high rate of viral variation that can be found in CTL epitopes of several HIV-1 proteins. However, viral persistence occurs despite continuous CTL recognition and although functional importance of conserved sites in the different HIV proteins may impose constraints to viral variation. In the reverse transcriptase (RT) which is a major target for antiretroviral therapy, the impact of the continuous pressure of drug therapy is more obvious than that of the CTLs. Shifts in immunodominant RT regions seem to allow the maintenance of the HIV-1 RT CTL recognition with disease progression and antiretroviral therapy. In respect to new highly active drug combinations, understanding the capacity of virus-specific CTLs to control residual viral variants seems very important and may allow development of efficient immunotherapies to prevent drug-induced viral resistance.