Plateau levels of viremia correlate with the degree of CD4+-T-cell loss in simian immunodeficiency virus SIVagm-infected pigtailed macaques: variable pathogenicity of natural SIVagm isolates

Abstract

Simian immunodeficiency virus from African green monkeys (SIVagm) results in asymptomatic infection in its natural host species. The virus is not inherently apathogenic, since infection of pigtailed (PT) macaques (Macaca nemestrina) with one isolate of SIVagm results in an immunodeficiency syndrome characterized by progressive CD4+-T-cell depletion and opportunistic infections. This virus was passaged once in a PT macaque and, thus, may not be entirely reflective of the virulence of the parental strain. The goal of the present study was to assess the pathogenicity of the PT-passaged isolate (SIVagm9063) and two primary SIVagm isolates in PT macaques, including the parental strain of the PT-passaged variant. Infection of macaques with any of the three isolates resulted in high levels of primary plasma viremia by 1 week after inoculation. Viremia was quickly controlled following infection with SIVagm155; these animals have maintained CD4+-T-cell subsets and remain healthy. The plateau levels among SIVagm90- and SIVagm9063-inoculated macaques varied widely from 100 to 1 million copies/ml of plasma. Three of four animals from each of these groups progressed to AIDS. Setpoint viremia and the degree of CD4+-T-cell loss at 6 months postinfection were not significantly different between macaques inoculated with SIVagm90 and SIVagm9063. However these parameters were significantly different in SIVagm155-inoculated macaques (P values of <0.01). Considering all the macaques, the degree of CD4+-T-cell loss by 6 months postinfection correlated with the plateau levels of viremia. Thus, similar to SIVsm/mac infection of macaques and human AIDS, viral load is an excellent prognostic indicator of disease course. The inherent pathogenicity of natural SIVagm isolates varies, but such natural isolates are capable of inducing AIDS in macaques without prior macaque passage.

FIG. 1.

Amino acid alignment of full-length envelope gene clones of SIVagm90, SIVagm9063, and SIVagm155. The amino acid sequence of the SIVagm9063 envelope clone is shown at the top in single-letter code, with dashes below indicating identical amino acids in aligned sequences, amino acid substitutions indicated, gaps introduced to maximize alignment shown by dots, and an asterisk to indicate a premature stop codon. The various variable and functional regions of the envelope gene (V1, V2, V3, V4, and V5) and TM domain are indicated.

FIG. 2.

Plasma viremia in SIVagm-infected PT macaques. All animals showed high levels of viral load by 1 week p.i. followed by a plateau (10² to 10⁵ copies of RNA/ml) at 8 to 12 weeks. Macaques inoculated with SIVagm9063 were more consistent in viral load, while lower plasma viremia was present in animals inoculated with SIVagm155. Macaques that were euthanized with profound CD4⁺-T-cell depletion are indicated by filled symbols.

FIG. 3.

SIV-expressing cells in lymph nodes at 1, 2, and 4 weeks after viral inoculation. The top panel shows the number of SIV-expressing cells counted per high power field (HPF) as the average cell number of 10 selected random fields. The bottom panels show representative ISH for SIV expression in sequential samples of lymph nodes from PT 9414, infected with SIVagm90.

FIG. 4.

Sequential alterations in CD4⁺ T cells in the peripheral blood of SIVagm-infected PT macaques throughout a 2.5-year period. CD4⁺ T cells in the blood are shown sequentially throughout infection with SIVagm90 (top), SIVagm9063 (middle), and SIVagm155 (bottom). Macaques that were euthanized with profound CD4⁺ T cell depletion are indicated by filled symbols.

FIG. 5.

Sequential alterations in CD8⁺ T cells and B cell subsets in the peripheral blood of SIVagm-infected PT macaques throughout a 2.5-year period. Top panels show absolute blood CD8⁺ T cells in SIVagm90 (left)-, SIVagm9063 (middle)-, and SIVagm155 (right)-infected macaques. The bottom panels show absolute B cell subsets. Macaques that were euthanized with profound CD4⁺ T cell depletion are indicated by filled symbols.

FIG. 6.

Correlation between plasma viral load and disease outcome. There is a significant correlation between viral load and the percent loss of CD4 cells by 6 months. Pearson correlation coefficient, r = −0.951; P value, <0.0001; vRNA, viral RNA.