Simian T-lymphotropic Virus-Associated Lymphoma in 2 Naturally Infected Baboons: T-cell Clonal Expansion and Immune Response during Tumor Development

Two young female baboons naturally infected with simian T-lymphotropic virus type 1 (STLV1) were euthanized due to chronic respiratory disease that was unresponsive to treatment. Massive lymphocytic infiltration of the lung interstitium suggested a diagnosis of STLV-associated lymphoma. In each case, the diagnosis was confirmed through inverse PCR (IPCR) that detected monoclonally integrated STLV1 provirus in cellular DNA extracted from lymphoma tissue and peripheral blood cells (PBC). One dominant STLV1-infected T-cell clone and 3 minor clones were detected in PBC from each baboon. Using archived PBC DNA and primers within the proviral genome and chromosomal DNA flanking the STLV1 integration sites in PCR analyses, we determined that the dominant clone in one baboon had first appeared approximately 8 mo after infection and had circulated for 4 y before clinical disease developed. ELISA testing of archived serum revealed that both baboons seroconverted to the p19 and p24 gag proteins and the envelope gp46 protein but not to the viral tax protein. Titers to p24 and gp46 rose significantly after infection and remained relatively constant until death, whereas titers to p19 increased with time. Although spontaneous STLV1-associated lymphomas have been described in baboons, the STLV1-associated lymphomas described here occurred in 2 relatively young baboons, both of whom had become infected with STLV at 3 to 4 y of age and developed lymphoma within 5 y of infection.Abbreviations: ATLL, adult T-cell lymphoma–leukemia, IPCR, inverse PCR, LTR, long terminal repeat, NHP, nonhuman primates, PBC, peripheral blood cells, STLV1, simian T-lymphotropic virus 1Simian T-lymphotropic virus type 1 (STLV1) belongs to a diverse group of deltaretroviruses that naturally infect over 20 species of African and Asian primates including baboons.^{4,19,21,23,27} STLV1 is closely related genetically to its human counterpart HTLV1, which infects over 20 million people worldwide.^8,29 Because of their close genetic relatedness, it has been postulated that HTLV1 arose from interspecies transmission of STLV1 from infected nonhuman primates (NHP) to humans.^19,29,36Lymphoma is the most common malignancy reported in NHP including baboons.^1-3,15 A causal association between STLV1 and lymphoma was suspected with the observation that most lymphomatous NHP also were latently infected with STLV1.^13,14,33 However, it was the presence of monoclonally integrated STLV1 provirus in malignant lymphocytes from lymphoma tissue that provided convincing evidence that STLV1 causes lymphoma–leukemia in NHP.^28,32 Most NHP infected with STLV1 remain asymptomatic; however, 1% to 2% of baboons develop STLV-associated lymphoma–leukemia, a malignancy that shares clinical and pathologic features with HTLV1-associated adult T-cell lymphoma–leukemia (ATLL) in humans.^1,14,28All STLV-associated lymphomas described in baboons thus far have arisen spontaneously; none have been induced by experimental inoculation with STLV1.³⁴ Outbreaks of lymphoma have been observed in large captive baboon colonies.^1,14,28,33 The Sukhumi outbreak, in which 300 cases of malignant lymphoma were recorded over a 30-y period, occurred within a captive colony of approximately 1500 sacred hamadryas baboons (Papio hamadryas). It is the largest and most intensively studied outbreak.^28,34 The Texas Biomedical Research Institute that houses about 3000 baboons of various species reported 98 cases of malignant lymphoma during a 15-y period.² In analyzing the data from the outbreak, one group¹ concluded that the percentage of STLV1-infected baboons that developed lymphoma during their lifetime was 1% to 2%. The median age at presentation of lymphoma in baboons was calculated to be 12.5 y.² These figures compare favorably with the development of ATLL in HTLV1-infected patients. Data from the cancer registries of Nagasaki Prefecture, Japan, suggest that the lifetime risk of developing ATLL among HTLV1-seropositive persons is 2.1% for women and 6.6% for men and that the median age at presentation of ATLL is 57.5 y.¹²We here describe 2 cases of STLV1-associated lymphoma–leukemia in 2 young baboons (8 and 9 y of age) that developed within 4 to 5 y of infection. Both monkeys had been enrolled in the same vaccine study when they were juveniles (12 to 18 mo of age) and became naturally infected with STLV1 soon after reaching sexual maturity at 3 to 4 y of age. Although the lymphomas arose spontaneously, the availability of archived serum samples and DNA from peripheral blood cells (PBC) allowed us to determine when and how these baboons had become infected, their immune response during infection, and the temporal appearance of malignant T-cell clones.