Highly restricted spread of HIV-1 and multiply infected cells within splenic germinal centers.
The tremendous dynamics of HIV infection finds expression in the tempo of sequence diversification. Genetic diversity calculations require the clearance of a majority of infected cells, the obvious predator being anti-HIV immune responses. Indeed, infiltration of germinal centers (GCs) by HIV-specific CD8(+) cytotoxic T lymphocytes has been described. A corollary to this description would be limited diffusion of virus within lymphoid structures. HIV efficiently infects and replicates mainly in activated CD4(+) T lymphoblasts. These cells are found within GCs after their activation in the adjacent periarteriolar lymphoid sheath (PALS). Here GCs and PALS have been dissected from consecutive 10-micrometer sections through splenic tissue from three HIV-1-infected patients. Nested PCR amplification of the two first hypervariable regions of the env gene indicated that 38-78% of sections contained HIV-infected cells. Since there are several hundred CD4(+) T cells per GC section, approximately 0.09-0.64% harbor proviral DNA. Such a low frequency not only suggests that virions on the follicular dendritic cell surfaces do not readily infect adjacent T cells but also indicates highly restricted spread of HIV within GCs and the PALS. Sections were heavily infiltrated by CD8(+) cells, which, together with a large body of extant data, suggests that the majority of infected cells are destroyed by HIV-specific cytotoxic T lymphocytes before becoming productively infected. Finally, sequence analysis revealed that those HIV-positive cells were multiply infected, which helps explain widespread recombination despite a low overall frequency of infected cells.
Gratton
S
S
Unité de Rétrovirologie Moléculaire, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
Cheynier
R
R
Dumaurier
M J
MJ
Oksenhendler
E
E
Wain-Hobson
S
S
D000595:Amino Acid Sequence; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology; D004279:DNA, Viral / Q000378:metabolism; D016679:Genome, Viral; D018858:Germinal Center / Q000821:virology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D017386:Sequence Homology, Amino Acid; D013154:Spleen / Q000166:cytology / Q000821:virology*
D004279:DNA, Viral; D015699:HIV Envelope Protein gp120