43 SARS-CoV-2 pulmonary abnormalities in macaques Finch et al. 3 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing an 44 exponentially increasing number of coronavirus disease 19 (COVID-19) cases 45 globally. Prioritization of medical countermeasures for evaluation in randomized 46 clinical trials is critically hindered by the lack of COVID-19 animal models that 47 enable accurate, quantifiable, and reproducible measurement of COVID-19 48 pulmonary disease free from observer bias. We first used serial computed 49 tomography (CT) to demonstrate that bilateral intrabronchial instillation of SARS-50 CoV-2 into crab-eating macaques (Macaca fascicularis) results in mild-to-moderate 51 lung abnormalities qualitatively characteristic of subclinical or mild-to-moderate 52 COVID-19 (e.g., ground-glass opacities with or without reticulation, paving, or 53 alveolar consolidation, peri-bronchial thickening, linear opacities) at typical 54 locations (peripheral>central, posterior and dependent, bilateral, multi-lobar). We 55 then used positron emission tomography (PET) analysis to demonstrate increased 56 FDG uptake in the CT-defined lung abnormalities and regional lymph nodes. 57 PET/CT imaging findings appeared in all macaques as early as 2 days post-58 exposure, variably progressed, and subsequently resolved by 6-12 days post-59 exposure. Finally, we applied operator-independent, semi-automatic quantification 60 of the volume and radiodensity of CT abnormalities as a possible primary endpoint 61 for immediate and objective efficacy testing of candidate medical countermeasures. 62 63

Human immunodeficiency virus and simian immunodeficiency virus (SIV) induce a slow progressive disease, characterized by the massive loss of memory CD4؉ T cells during the acute infection followed by a recovery phase in which virus replication is partially controlled. However, because the initial injury is so severe and virus production persists, the immune system eventually collapses and a symptomatic fatal disease invariably occurs. We have assessed CD4؉ T-cell dynamics and disease progression in 12 SIV-infected rhesus monkeys for nearly 2 years. Three macaques exhibiting a rapid progressor phenotype experienced rapid and irreversible loss of memory, but not naïve, CD4؉ T lymphocytes from peripheral blood and secondary lymphoid tissues and died within the first 6 months of virus inoculation. In contrast, SIV-infected conventional progressor animals sustained marked but incomplete depletions of memory CD4 ؉ T cells and continuous activation/proliferation of this T-lymphocyte subset. This was associated with a profound loss of naïve CD4 ؉ T cells from peripheral blood and secondary lymphoid tissues, which declined at rates that correlated with disease progression. These data suggest that the persistent loss of memory CD4 ؉ T cells, which are being eliminated by direct virus killing and activation-induced cell death, requires the continuous differentiation of naïve into memory CD4 ؉ T cells. This unrelenting replenishment process eventually leads to the exhaustion of the naïve CD4 ؉ T-cell pool and the development of disease.

The great difficulty in eliciting broadly cross-reactive neutralizing antibodies (NAbs) against human immunodeficiency virus type 1 (HIV-1) isolates has been attributed to several intrinsic properties of their viral envelope glycoprotein, including its complex quaternary structure, extensive glycosylation, and marked genetic variability.

Since the earliest days of the HIV epidemic, the number of CD4 ؉ T cells per unit volume of blood has been recognized as a major prognostic factor for the development of AIDS in persons with HIV infection. It has also been generally accepted that approximately 2% of total body lymphocytes circulate in the blood. In the present study, we have used a nondepleting humanized anti-CD4 monoclonal antibody labeled with the gamma emitter indium-111 to visualize the CD4 ؉ T-cell pool in vivo in nonhuman primates with simian HIV infection. A strong correlation was noted between radiotracer uptake in spleen, tonsil, axillary lymph nodes, and peripheral blood CD4 T-cell counts ( ‫؍‬ 0.75, 0.93, and 0.85, respectively, P < .005). The relationship between radiotracer retention in lymphoid tissues and CD4 ؉ T-cell counts in the circulation was governed by an exponential law. These data provide an estimate for the total number of lymphocytes in the body as being between 1.9 and 2.9 ؋ 10 12 and suggest that the partition between peripheral blood and lymphoid tissue is between 0.3% and 0.5%. (Blood. 2009; 114:328-337)