We establish a promising NHP model by addressing the following: 1) genetic and immunological variability in subspecies, 2) inoculum dose, 3) inoculum route, 4) virulent strain of virus isolated from patient, and 5) demographic background of primates, that could investigate the interaction between SARS-CoV-2 and a similar immune system of humans. We exposed macaques to high titres of SARS-CoV-2, via intratracheal, oral, conjunctival, intranasal, and intravenous route. All macaques had acute interstitial pneumonia with endotheliitis in the lungs and a significant loss of total lymphocytes. After viral challenges, all live animals were subjected to swab sampling of nasopharyngeal, oropharyngeal, conjunctival, and rectal tissues. All macaques were euthanized and necropsied 3 days post infection. Upon necropsy, tissue samples, including respiratory, immune, intestinal, cardiovascular, and reproductive organs were examined. Post-mortem examination showed multifocal, bright red lesions in the upper, middle, and lower lobes of the lungs. Upper and lower respiratory tracts were the predominant sites of virus replication. Low viral levels were present in most other organs and not detected in plasma at any time point. All macaques had a significant loss of total lymphocytes, including CD4+ and CD8+ T cells, B cells, and NK cells during early infection. Similarly, lymphopenia was reported in 83.2% of hospitalized SARS-CoV-2 patients. The alteration of peripheral lymphocyte subsets seems to be correlated with severe clinical cases. Therefore, the NHP model may be used to validate the effect of immune modulators in combination with therapeutic approaches to improve lymphopenia.