https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)71142-9.pdf

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

Clinical evidence suggests that cellular immunity is involved in controlling human immunodeficiency virus-1 (HIV-1) replication. An animal model of acquired immune deficiency syndrome (AIDS), the simian immunodeficiency virus (SIV)-infected rhesus monkey, was used to show that virus replication is not controlled in monkeys depleted of CD8+ lymphocytes during primary SIV infection. Eliminating CD8+ lymphocytes from monkeys during chronic SIV infection resulted in a rapid and marked increase in viremia that was again suppressed coincident with the reappearance of SIV-specific CD8+ T cells. These results confirm the importance of cell-mediated immunity in controlling HIV-1 infection and support the exploration of vaccination approaches for preventing infection that will elicit these immune responses.

https://science.sciencemag.org/content/sci/283/5403/857.full.pdf

Control of Viremia in Simian Immunodeficiency Virus Infection by CD8+ Lymphocytes

Counting Antigen-Specific CD8 T Cells: A Reevaluation of Bystander Activation during Viral Infection

HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T-cells

The viruses HIV-1, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and hepatitis C virus (HCV) are characterized by the establishment of lifelong infection in the human host, where their replication is thought to be tightly controlled by virus-specific CD8+ T cells. Here we present detailed studies of the differentiation phenotype of these cells, which can be separated into three distinct subsets based on expression of the costimulatory receptors CD28 and CD27. Whereas CD8+ T cells specific for HIV, EBV and HCV exhibit similar characteristics during primary infection, there are significant enrichments at different stages of cellular differentiation in the chronic phase of persistent infection according to the viral specificity, which suggests that distinct memory T-cell populations are established in different virus infections. These findings challenge the current definitions of memory and effector subsets in humans, and suggest that ascribing effector and memory functions to subsets with different differentiation phenotypes is no longer appropriate.

Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections.

Virologic and immunologic studies were performed on five patients presenting with primary human immunodeficiency virus type 1 (HIV-1) infection. CD8+ cytotoxic T lymphocyte (CTL) precursors specific for cells expressing antigens of HIV-1 Gag, Pol, and Env were detected at or within 3 weeks of presentation in four of the five patients and were detected in all five patients by 3 to 6 months after presentation. The one patient with an absent initial CTL response had prolonged symptoms, persistent viremia, and low CD4+ T-cell count. Neutralizing antibody activity was absent at the time of presentation in all five patients. These findings suggest that cellular immunity is involved in the initial control of virus replication in primary HIV-1 infection and indicate a role for CTL in protective immunity to HIV-1 in vivo.

Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.

HIV-1 envelope-specific CTL clones were isolated from the peripheral blood of two patients from within weeks of seroconversion. These clones were CD8+ and restricted by the HLA-B7 molecule. The minimum epitope recognized by the clones was determined to be the 30-amino acid (aa) sequence RPNNNTRKSI within the third variable (V3) loop of the envelope glycoprotein gp120. The aa sequence of this epitope is consistent with the motif found in naturally processed peptides eluted from HLA-B7 molecules. This region of the V3 loop is reasonably well conserved among clade B and some nonclade B isolates of HIV-1, especially at the anchor residues that determine binding to the HLA-B7 molecule. Using peptides based upon virus sequences present within each patient, we determined that autologous viruses were recognized by the clones, and we detected no escape variants from the initial clonal response during the acute phase of infection. Interestingly, a serine to arginine change at position 9 of the epitope abrogated clone recognition in one of the patients. This aa change is one factor that has been associated with a change from a nonsyncytium-inducing to a syncytium-inducing phenotype of HIV-1, raising the possibility that in HLA-B7-expressing patients, escape from this clonal CTL response and a change in viral phenotype may be linked. This study demonstrates that human CTL can be generated against sequences within the third variable loop of HIV-1 gp120. Because multiple vaccine strategies are based upon the V3 loop of HIV-1 gp120, this defined epitope can be exploited in determining the ability of certain vaccines to stimulate a CTL response in a select population of individuals.

C. A. Andrews

Papers

Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.

A region of the third variable loop of HIV-1 gp120 is recognized by HLA-B7-restricted CTLs from two acute seroconversion patients.