HIV and its complications account for roughly 7 to 10 percent of microbiology and immunology questions on the current NBME Step 1 content outline, which makes it the single highest yield infectious disease topic on the exam.
The NBME tests HIV across four predictable lanes: structure and replication, the CDC diagnostic algorithm, the CD4 count linked opportunistic infection ladder, and the mechanism of each antiretroviral class. We have taught thousands of IMGs preparing for Step 1, and the candidates who consistently score in the top quartile share one habit. They do not memorize HIV facts in isolation. They build a single mechanistic story that connects the virion, the CD4 cell, the immune collapse, and the treatment.
This guide gives you that story. We cover every subtopic an IMG searches when preparing for HIV vignettes, in the order the NBME tests them, with the mnemonics, comparison tables, and labeled diagrams that actually stick under exam pressure.
HIV-1 is an enveloped, single stranded, positive sense RNA retrovirus in the Lentivirus genus of the Retroviridae family. The virion measures 100 to 120 nanometers in diameter and carries two identical copies of its RNA genome inside a conical capsid built from p24 protein. Every structural component of HIV has a Step 1 implication.
Figure 1. HIV-1 virion architecture. The gp120 spike binds CD4 first, then engages CCR5 or CXCR4 to trigger fusion via gp41. p24 is the antigen detected on 4th generation testing.
• gp120 (Surface glycoprotein): binds the CD4 receptor on T helper cells, macrophages, and dendritic cells. Conformational change after CD4 binding exposes a second binding site for the chemokine coreceptor CCR5 or CXCR4. Macrophage tropic strains use CCR5 (early infection) : T cell tropic strains use CXCR4 (late infection, more pathogenic).
• gp41 (Transmembrane glycoprotein): drives the fusion of the viral envelope with the host cell membrane. This is the target of enfuvirtide, the prototypic fusion inhibitor.
• p24 (Capsid protein): forms the conical core. p24 antigen is what the 4th generation immunoassay detects directly in serum, allowing diagnosis before antibody seroconversion. This is the single most testable structural fact about HIV.
• p17 (Matrix protein): lines the inner envelope and anchors the gp41 and gp120 spike complex.
• Reverse transcriptase, Integrase, Protease: three packaged enzymes that drive replication. Each is the target of a different drug class.
| High Yield Pearl: CCR5 delta 32 CCR5 delta 32 homozygous mutation makes individuals essentially immune to R5 strain HIV infection. CCR5 delta 32 heterozygotes have slower disease progression. This is a classic Step 1 distractor in genetics vignettes about HIV resistance. |
The HIV replication cycle is a seven step sequence. Every antiretroviral drug class blocks exactly one of these seven steps. If you know the cycle, you know the pharmacology. The NBME loves testing this as a mechanism question, not a name recall question.
Figure 2. The seven step HIV replication cycle. Each step is paired with the antiretroviral class that targets it. Standard first line ART uses 2 NRTIs plus 1 INSTI.
1. Attachment. gp120 on the virion binds the CD4 receptor on the host cell.
2. Coreceptor binding and fusion. Bound gp120 undergoes a conformational change exposing the V3 loop, which engages CCR5 (macrophages) or CXCR4 (T cells). gp41 then drives fusion of the viral and cellular membranes, releasing the viral core into the cytoplasm.
3. Reverse transcription. Reverse transcriptase converts the viral RNA genome into double stranded DNA. This step is error prone with no proofreading, which is the source of HIV genetic diversity and drug resistance.
4. Integration. Integrase inserts the proviral DNA into the host genome. Once integrated, the virus is permanent in that cell line. This is why HIV cannot be cured with current therapy. Latent proviral DNA persists in long lived memory CD4 cells.
5. Transcription and translation. Host RNA polymerase II transcribes the provirus. Tat and Rev (regulatory proteins) accelerate transcription and nuclear export. Host ribosomes translate the proteins.
6. Assembly and protease cleavage. Gag and Gag-Pol polyproteins assemble at the inner membrane. HIV protease cleaves these polyproteins into functional units (p17, p24, reverse transcriptase, integrase). Without protease cleavage, the virion remains immature and non infectious.
7. Budding and maturation. The new virion buds from the cell, acquiring its lipid envelope from the host membrane along with embedded gp120 and gp41 spikes. The mature virion then infects another CD4 cell.
| Drug class | Target | Examples | Step 1 buzzword |
| CCR5 antagonist | Blocks CCR5 coreceptor | Maraviroc | Tropism testing required before use |
| Fusion inhibitor | Blocks gp41 fusion | Enfuvirtide | Only injectable ART (subcutaneous): salvage therapy |
| NRTI | Chain termination of RT | Tenofovir, emtricitabine, abacavir, zidovudine, lamivudine | Tenofovir = renal/bone tox. Abacavir = HLA B*5701 |
| NNRTI | Allosteric RT inhibition | Efavirenz, nevirapine, rilpivirine | Efavirenz = vivid dreams, teratogenic |
| INSTI | Blocks integration | Dolutegravir, bictegravir, raltegravir | First line. High barrier to resistance. Weight gain |
| Protease inhibitor | Blocks protease cleavage | Darunavir, atazanavir, ritonavir, lopinavir | Ritonavir = CYP3A4 booster. Hyperlipidemia, lipodystrophy |
| Mnemonic: “Stop Viruses From Replicating Inside The Body” S top attachment (Maraviroc, CCR5 antagonist) V iruses blocked at gp41 fusion (Enfuvirtide) F orbid reverse transcription (NRTIs and NNRTIs) R ound up at integRase (Dolutegravir, Bictegravir, Raltegravir) I nhibit protease cleavage (Darunavir, Atazanavir, Ritonavir) B lock budding maturation (cycle ends here) |
| Standard first line ART regimen Modern first line therapy combines 2 NRTIs plus 1 INSTI. The most common single tablet combination is bictegravir plus tenofovir alafenamide plus emtricitabine (Biktarvy). Dolutegravir based regimens are equally favored. Patients on effective ART achieve viral suppression below 50 copies per mL and become functionally non infectious (U equals U: Undetectable equals Untransmittable). |
NBME vignettes love testing per exposure transmission risk because the numbers are counterintuitive. Most candidates overestimate sexual transmission risk and underestimate vertical transmission risk. Memorize the order.
Figure 3. HIV transmission routes ranked by per exposure risk, with matched prevention strategies for each route.
• Contaminated blood transfusion: highest per exposure risk at approximately 93 percent. Now essentially eliminated in the US through donor nucleic acid testing.
• Vertical (mother to child) transmission: 25 percent without intervention, less than 1 percent with maternal ART plus elective cesarean section plus formula feeding. Always test neonates with HIV DNA PCR, never antibody testing. Maternal IgG crosses the placenta.
• Receptive anal intercourse: highest sexual transmission risk at 1.4 percent per act because the rectal mucosa is thin and rich in immune target cells.
• Needlestick injury: 0.23 percent (less than 1 in 300). For comparison: hepatitis B virus transmits at approximately 30 percent per needlestick, hepatitis C virus at approximately 3 percent. HIV is the least transmissible of the three through occupational exposure.
• Vaginal intercourse: 0.08 percent per act for the receptive female partner. Risk multiplies several fold in the presence of ulcerative sexually transmitted infections (syphilis, HSV-2, chancroid).
| PrEP vs PEP: a frequent NBME distinction PrEP (pre exposure prophylaxis): daily tenofovir plus emtricitabine in high risk individuals. Reduces sexual transmission by approximately 99 percent with full adherence. Long acting injectable cabotegravir is approved every 2 months. PEP (post exposure prophylaxis): 28 day course of tenofovir plus emtricitabine plus dolutegravir or raltegravir. Must start within 72 hours of exposure (sooner is better). |
The CDC updated the HIV diagnostic algorithm in 2014, retiring the old ELISA followed by Western blot sequence. The current algorithm starts with a 4th generation combination immunoassay, which detects both p24 antigen and anti HIV antibodies. This shortens the window period by approximately 7 to 10 days compared to the antibody only third generation tests.
Figure 4. The CDC HIV diagnostic algorithm. Screen with 4th generation immunoassay, confirm with antibody differentiation, then use HIV RNA for discordant results.
• p24 antigen (free viral capsid protein in serum, appears 14 to 21 days after infection)
• Anti HIV-1 antibodies (IgM and IgG, appear 21 to 28 days after infection)
• Anti HIV-2 antibodies (relevant for West African exposure)
Step 1. Screen with 4th generation immunoassay.
Step 2. If reactive: confirm with HIV-1 and HIV-2 antibody differentiation assay (Multispot or Geenius). This replaces the older Western blot.
Step 3. If screening is reactive but the differentiation assay is negative or indeterminate (a discordant result), order HIV-1 RNA by PCR. A positive RNA confirms acute infection that has not yet seroconverted.
| The “negative” pitfall A patient with high pretest probability and a negative 4th generation test still might have very early acute infection (less than 14 days post exposure). If clinical suspicion is high, order HIV RNA directly. HIV RNA is detectable 10 to 12 days after exposure, earlier than any antigen or antibody marker. |
Maternal IgG crosses the placenta. A baby born to an HIV positive mother will have a positive HIV antibody test for up to 18 months regardless of true infection status. Diagnose neonates with HIV DNA PCR at birth, 1 month, and 4 months. Two negative PCRs after 1 month of age effectively rule out vertical transmission. This is a classic Step 1 question stem.
Untreated HIV infection follows a predictable three phase course over years to decades. The NBME tests this curve by asking what clinical findings and lab values appear at each timepoint.
Figure 5. CD4 count (blue) inversely tracks viral load (red) over the course of untreated HIV infection. The viral setpoint at 6 to 12 months predicts the speed of progression.
Within 2 to 6 weeks of infection, 50 to 90 percent of patients develop a mononucleosis like illness with fever, generalized lymphadenopathy, pharyngitis, maculopapular rash on the trunk, and sometimes aseptic meningitis. Viral load peaks at 10^6 to 10^7 copies per mL. CD4 count drops transiently then partially recovers. The vignette buzzword is “young patient with mono like illness, negative monospot, recent unprotected sexual exposure.”
After acute infection, the immune response brings viral load down to a setpoint (typically 10^3 to 10^5 copies per mL). The setpoint predicts progression. Higher setpoint, faster decline. CD4 count drops at approximately 50 to 100 cells per microliter per year untreated. Patients are asymptomatic or have persistent generalized lymphadenopathy. This phase lasts an average of 8 to 10 years without treatment.
AIDS is diagnosed by either a CD4 count below 200 cells per microliter or the appearance of an AIDS defining illness regardless of CD4 (for example, esophageal candidiasis, PCP, Kaposi sarcoma, primary CNS lymphoma). Viral load spikes again as the immune system collapses. Median survival without ART is 2 to 3 years from AIDS diagnosis.
This single concept generates more Step 1 questions than any other HIV topic. The pattern: a vignette gives you a CD4 count and you predict which infection. Or a vignette gives you the infection and you predict the CD4 count. Master the ladder and you will reflexively answer these vignettes in under 30 seconds.
Figure 6. CD4 count thresholds and the opportunistic infections that emerge at each level. Prophylaxis cutoffs are marked: TMP SMX at CD4 less than 200 for PCP: azithromycin at CD4 less than 50 for MAC.
The patient acts immunocompetent. Same infections you would expect in the general population. No opportunistic prophylaxis indicated.
• Oral candidiasis (thrush): white plaques on tongue and buccal mucosa that scrape off, revealing erythematous bases. Caused by Candida albicans.
• Oral hairy leukoplakia: white corrugated plaques on lateral tongue that do NOT scrape off. Caused by EBV. Pathognomonic for HIV.
• Kaposi sarcoma: purple papules on skin or mucosa. Caused by HHV-8. Classic AIDS defining malignancy.
• VZV reactivation (shingles), especially multidermatomal or recurrent.
• Tuberculosis (classic pulmonary presentation) occurs at relatively preserved CD4.
• Recurrent bacterial pneumonia: Streptococcus pneumoniae, Haemophilus influenzae.
• Recurrent vaginal candidiasis.
• Pneumocystis jirovecii pneumonia (PCP): the prototypic AIDS pneumonia. Bilateral interstitial infiltrates (ground glass on CT), elevated LDH, profound hypoxemia disproportionate to chest x-ray findings. Diagnose by induced sputum or bronchoalveolar lavage with silver stain (cup or saucer shaped cysts). Treat with TMP SMX plus steroids if PaO2 less than 70 mmHg.
• Endemic mycoses: Histoplasma capsulatum (Ohio and Mississippi River valleys, bird and bat exposure), Coccidioides immitis (southwestern US, Valley fever), Blastomyces (eastern US river valleys).
• JC virus PML: progressive focal neurologic deficits, non enhancing white matter lesions on MRI.
• HIV wasting syndrome and HIV associated dementia.
• Toxoplasma gondii encephalitis: multiple ring enhancing lesions on contrast MRI, headache, focal neurologic deficits. Treat with sulfadiazine plus pyrimethamine plus leucovorin. Differential: primary CNS lymphoma (single lesion, EBV positive on CSF PCR).
• Cryptococcus neoformans meningitis: subacute meningitis. Diagnose with India ink stain (capsule shows up as a halo) or cryptococcal capsular antigen in CSF or serum. Treat with amphotericin B plus flucytosine, then fluconazole maintenance.
• Primary CNS lymphoma: single ring enhancing lesion (versus multiple in toxoplasma). EBV driven. Diagnose by CSF PCR for EBV plus brain biopsy.
• Bartonella bacillary angiomatosis: red vascular skin lesions that can mimic Kaposi sarcoma. Caused by Bartonella henselae or quintana. Treat with erythromycin or doxycycline.
• Mycobacterium avium complex (MAC): disseminated infection with fever, weight loss, hepatosplenomegaly, anemia, elevated alkaline phosphatase. Treat with clarithromycin or azithromycin plus ethambutol plus rifabutin. Start azithromycin prophylaxis when CD4 falls below 50.
• CMV retinitis: blurred vision, floaters. Funduscopy shows pizza pie appearance with hemorrhages and exudates. Treat with ganciclovir or valganciclovir. CMV also causes esophagitis (large solitary ulcer with owl eye inclusions) and colitis.
• Cryptosporidium and microsporidia: chronic watery diarrhea. Diagnose with acid fast stains of stool. No reliably effective treatment. Key intervention is ART to restore immunity.
• Aspergillus: invasive pulmonary aspergillosis, especially in advanced AIDS.
| Mnemonic: “OBESE” for the CD4 ladder O ral candidiasis and Oral hairy leukoplakia (CD4 200 to 500) B acterial pneumonia, B cell lymphoma, reactivation TB (CD4 200 to 500) E sophageal candidiasis and PCP pneumonia (CD4 less than 200) S omething neuro (Toxoplasma, Cryptococcus, JC virus PML, CNS lymphoma) at CD4 less than 100 E verything else (MAC, CMV, Cryptosporidium) at CD4 less than 50 |
| CD4 threshold | Pathogen | First line prophylaxis | Stop when |
| Less than 200 | Pneumocystis jirovecii | TMP SMX one DS tablet daily | CD4 above 200 for 3 months on ART |
| Less than 100 (Toxo IgG positive) | Toxoplasma gondii | TMP SMX (same drug covers both) | CD4 above 200 for 3 months on ART |
| Less than 50 | Mycobacterium avium complex | Azithromycin 1200 mg weekly | CD4 above 100 for 3 months on ART |
Step 1 questions rarely say “the patient has HIV.” They describe a clinical scenario and expect you to recognize the immune deficit. Here are the patterns we see most often.
Stem: young adult with fever, rash, sore throat, lymphadenopathy, recent unprotected sex or new partner. Monospot negative. EBV serology negative. Answer: acute retroviral syndrome. Confirm with HIV RNA (not antibody, which has not yet seroconverted).
Stem: AIDS patient with subacute dyspnea, dry cough, low oxygen saturation, bilateral ground glass infiltrates on CT, elevated LDH. Answer: Pneumocystis jirovecii pneumonia. Diagnose with silver stain (cup or saucer cysts) on BAL. Treat with TMP SMX. Add steroids if PaO2 less than 70 or A-a gradient greater than 35.
Multiple ring enhancing lesions equals Toxoplasma gondii (treat empirically with sulfadiazine plus pyrimethamine. Biopsy only if no improvement in 2 weeks). Single ring enhancing lesion equals primary CNS lymphoma (EBV positive on CSF PCR. Diagnose with brain biopsy).
Stem: AIDS patient with weeks of headache, low grade fever, mild meningismus. India ink stain shows yeast with halo. Answer: Cryptococcus neoformans. Treat with amphotericin B plus flucytosine induction, then fluconazole.
CD4 less than 50. Funduscopy shows hemorrhages and exudates (pizza pie). Answer: CMV retinitis. Treat with ganciclovir or valganciclovir.
Most common cause: esophageal candidiasis (treat empirically with fluconazole). If symptoms persist on fluconazole, endoscopy: large solitary ulcer with owl eye nuclear inclusions equals CMV (ganciclovir). Multiple small ulcers equals HSV (acyclovir).
Stem: hollow bore needlestick from HIV positive source. Answer: start PEP within 72 hours. Standard regimen: tenofovir plus emtricitabine plus dolutegravir (or raltegravir) for 28 days. Baseline HIV test at exposure, follow up at 6 weeks, 12 weeks, and 6 months.
Start ART immediately regardless of CD4 count. Goal: undetectable viral load before delivery. Mode of delivery: vaginal if viral load less than 1000 copies per mL near delivery, cesarean if higher. Avoid breastfeeding. Treat neonate with zidovudine for 4 to 6 weeks. Vertical transmission risk drops from 25 percent to less than 1 percent with this protocol.
The NBME content outline post 2022 has shifted toward mechanism integration over rote recall. Recent forms test HIV in several new ways:
• Cross disciplinary vignettes combining HIV pharmacology with renal (tenofovir Fanconi syndrome), genetics (abacavir HLA B*5701 hypersensitivity), endocrine (PI induced lipodystrophy and insulin resistance), and CNS pharmacology (efavirenz neuropsychiatric effects).
• Increased emphasis on PrEP and PEP guidelines, including the long acting injectable cabotegravir option approved every 2 months.
• Frequent testing of the 4th generation algorithm and the window period for each marker.
• Integration of HIV with immunology: Th1 and Th2 balance, the role of CCR5 in HIV resistance, and the molecular basis of immune escape.
• Reduced focus on older drugs (zidovudine monotherapy, didanosine, stavudine) and increased focus on first line INSTI based regimens.
| Where IMGHH fits in Our structured Step 1 prep program builds exactly the kind of cross system mechanistic thinking the new NBME forms reward. We do not teach you to memorize lists. We teach you the immune deficit, the matching pathogen, and the drug mechanism in one connected story. |
| Feature | Toxoplasmosis | CNS lymphoma | PML (JC virus) |
| CD4 count | Less than 100 | Less than 50 | Less than 200 |
| Number of lesions | Multiple | Single (usually) | Multiple white matter |
| Enhancement | Ring enhancing | Ring enhancing | Non enhancing |
| CSF EBV PCR | Negative | Positive | Negative |
| CSF JC virus PCR | Negative | Negative | Positive |
| Treatment | Sulfadiazine + pyrimethamine + leucovorin | Methotrexate + ART | Restore immunity with ART |
| Feature | Candida esophagitis | CMV esophagitis | HSV esophagitis |
| Most common cause | Yes (most common overall) | Less common | Less common |
| Endoscopic findings | White plaques | Linear deep ulcers (large, solitary) | Multiple small punched out ulcers |
| Histology | Pseudohyphae | Owl eye intranuclear inclusions | Multinucleated giant cells, eosinophilic inclusions |
| Treatment | Fluconazole | Ganciclovir or valganciclovir | Acyclovir or valacyclovir |
| Drug | Distinguishing side effect |
| Zidovudine (AZT) | Bone marrow suppression (macrocytic anemia, neutropenia), myopathy |
| Tenofovir disoproxil | Nephrotoxicity (Fanconi syndrome), bone loss (osteomalacia) |
| Abacavir | HLA B*5701 hypersensitivity (fatal on rechallenge) |
| Didanosine, stavudine (older NRTIs) | Lactic acidosis, peripheral neuropathy, pancreatitis |
| Efavirenz (NNRTI) | Vivid dreams, neuropsychiatric symptoms, false positive cannabinoid screen, teratogenic |
| Nevirapine (NNRTI) | Hepatotoxicity (especially women with CD4 above 250), Stevens Johnson syndrome |
| Protease inhibitors (class effect) | Hyperlipidemia, lipodystrophy (buffalo hump, central obesity, lipoatrophy), insulin resistance |
| Indinavir (PI) | Crystal nephropathy, kidney stones |
| Atazanavir (PI) | Unconjugated hyperbilirubinemia (Gilbert like, benign) |
| Ritonavir (PI) | Strong CYP3A4 inhibitor (used as booster), GI side effects |
| Dolutegravir, bictegravir (INSTIs) | Weight gain, possible neural tube defects if conceived on dolutegravir (older data) |
These questions mirror the difficulty and structure of recent NBME forms. Do them under timed conditions, then read every explanation including the distractors.
Question 1.
A 24 year old man presents with fever, sore throat, generalized lymphadenopathy, and a maculopapular rash on his trunk for the past 6 days. He had unprotected sex with a new partner 3 weeks ago. Monospot is negative. EBV IgM is negative. Which of the following tests is most likely to be positive at this stage?
A. HIV antibody by 3rd generation ELISA
B. HIV Western blot
C. HIV-1 RNA by PCR
D. Cytomegalovirus IgG
E. Streptococcal throat culture
Answer: C. HIV-1 RNA by PCR
Explanation: This is acute retroviral syndrome. HIV RNA is detectable 10 to 12 days after infection, before either p24 antigen or antibody. At 3 weeks, antibody tests (A and B) are often still negative. CMV (D) can cause a mono like illness but the recent unprotected sex with rash and lymphadenopathy strongly suggests HIV. (E) is unlikely given the rash and systemic symptoms.
Question 2.
A 38 year old woman with AIDS (CD4 count 35 cells per microliter) presents with 2 weeks of blurred vision and floaters in the right eye. Funduscopic examination reveals scattered hemorrhages and exudates with a pizza pie appearance. Which of the following is the most appropriate initial therapy?
A. Acyclovir
B. Amphotericin B
C. Ganciclovir
D. Fluconazole
E. TMP SMX
Answer: C. Ganciclovir
Explanation: CMV retinitis classically presents with floaters and the pizza pie fundus at CD4 less than 50. Treat with intravenous ganciclovir or oral valganciclovir. Acyclovir (A) treats HSV and VZV, not CMV (CMV lacks the thymidine kinase needed to activate acyclovir). Amphotericin B (B) and fluconazole (D) treat Cryptococcus and Candida. TMP SMX (E) treats PCP and Toxoplasma.
Question 3.
A 42 year old man with newly diagnosed HIV has a CD4 count of 145 cells per microliter. Toxoplasma IgG is positive. Which of the following prophylactic regimens is most appropriate?
A. Azithromycin weekly
B. Fluconazole daily
C. Isoniazid daily for 9 months
D. TMP SMX one double strength tablet daily
E. No prophylaxis needed
Answer: D. TMP SMX one double strength tablet daily
Explanation: CD4 less than 200 equals start PCP prophylaxis with TMP SMX. The same drug also covers Toxoplasma reactivation, which is the second concern when Toxo IgG is positive and CD4 falls below 100. Azithromycin (A) is for MAC at CD4 less than 50. Fluconazole (B) is not standard primary prophylaxis. Isoniazid (C) is for latent TB.
Question 4.
A 31 year old man with AIDS presents with a 3 week history of progressive right sided weakness and headache. CD4 count is 75 cells per microliter. Contrast MRI shows multiple ring enhancing lesions in the basal ganglia and cortex. Which of the following is the most likely diagnosis?
A. Primary CNS lymphoma
B. Toxoplasma gondii encephalitis
C. Cryptococcus neoformans meningitis
D. Progressive multifocal leukoencephalopathy
E. HIV associated dementia
Answer: B. Toxoplasma gondii encephalitis
Explanation: Multiple ring enhancing lesions at CD4 less than 100 in an HIV patient is Toxoplasma until proven otherwise. Primary CNS lymphoma (A) classically shows a single ring enhancing lesion. Cryptococcus (C) causes meningitis, not parenchymal masses. PML (D) shows non enhancing white matter lesions. HIV dementia (E) is a clinical diagnosis without focal MRI lesions. Treat empirically with sulfadiazine plus pyrimethamine plus leucovorin and reassess in 2 weeks.
Question 5.
A baby is born to a mother with newly diagnosed HIV. The mother received no antenatal ART. Which of the following tests should be used to confirm or rule out HIV infection in this neonate at 1 month of age?
A. 4th generation HIV antigen and antibody immunoassay
B. HIV-1 and HIV-2 antibody differentiation assay
C. HIV Western blot
D. HIV DNA PCR
E. p24 antigen by ELISA
Answer: D. HIV DNA PCR
Explanation: Maternal IgG crosses the placenta and can persist in the infant up to 18 months. Any antibody based test (A, B, C) will be positive regardless of true infection status. p24 antigen (E) has poor sensitivity in neonates. HIV DNA PCR detects integrated proviral DNA in the infant’s own cells and is the test of choice. Standard schedule: PCR at birth, 1 month, and 4 months.
Question 6.
A 28 year old nurse sustains a hollow bore needlestick injury while drawing blood from a patient with HIV. The source patient has a viral load of 50,000 copies per mL. Which of the following is the most appropriate next step?
A. Wait for the nurse’s baseline HIV test result before deciding
B. Start tenofovir plus emtricitabine plus dolutegravir within 72 hours
C. Start zidovudine monotherapy for 28 days
D. Administer HIV immune globulin
E. No prophylaxis is needed because risk of transmission is less than 1 percent
Answer: B. Start tenofovir plus emtricitabine plus dolutegravir within 72 hours
Explanation: Post exposure prophylaxis (PEP) should start as soon as possible, ideally within hours and definitely within 72 hours of exposure. Standard regimen is two NRTIs plus an INSTI for 28 days. Do not wait for baseline testing (A). Zidovudine monotherapy (C) is obsolete. HIV immune globulin (D) does not exist as a prophylactic. Although per exposure risk is low (E), the consequences of seroconversion warrant PEP for every documented exposure.
Question 7.
A 45 year old man with AIDS (CD4 80 cells per microliter) presents with subacute dyspnea, nonproductive cough, and oxygen saturation of 86 percent on room air. Chest CT shows bilateral ground glass opacities. LDH is markedly elevated. Bronchoalveolar lavage with silver stain reveals cup shaped cysts. Which of the following is the most appropriate treatment?
A. Azithromycin alone
B. Ceftriaxone plus azithromycin
C. Levofloxacin
D. TMP SMX
E. TMP SMX plus prednisone
Answer: E. TMP SMX plus prednisone
Explanation: This is PCP. First line treatment is TMP SMX. Adjunctive steroids are indicated when PaO2 is less than 70 mmHg on room air or the A-a gradient exceeds 35, because steroids reduce mortality by blunting the inflammatory response to dying organisms. SpO2 of 86 percent suggests severe hypoxemia. (D) alone is incomplete. (A, B, C) treat typical community acquired pneumonias, not PCP.
Question 8.
A 35 year old woman with HIV starts a new antiretroviral regimen. Three weeks later, she develops fever, malaise, and a diffuse maculopapular rash. Her HLA B*5701 status had not been checked before initiation. Which of the following drugs is most likely responsible?
A. Abacavir
B. Dolutegravir
C. Efavirenz
D. Emtricitabine
E. Tenofovir
Answer: A. Abacavir
Explanation: Abacavir hypersensitivity reaction is strongly linked to HLA B*5701. Patients of this genotype have a roughly 50 percent risk of severe hypersensitivity (fever, rash, GI symptoms, respiratory distress), which can be fatal on rechallenge. All patients must be screened for HLA B*5701 before starting abacavir. Efavirenz (C) causes neuropsychiatric symptoms and rash but is not associated with HLA B*5701. Tenofovir (E) causes renal injury and bone loss. Dolutegravir (B) causes weight gain.
Question 9.
A 50 year old man with HIV on long term efavirenz and tenofovir plus emtricitabine presents with a 3 month history of progressive bone pain and fatigue. Labs show serum creatinine of 1.8 mg per dL (baseline 0.9), phosphorus of 1.8 mg per dL, urine glucose positive despite normal serum glucose, and proteinuria. Which of the following mechanisms best explains his presentation?
A. Acute interstitial nephritis
B. Hyperuricemia from indinavir
C. Proximal renal tubular dysfunction (Fanconi syndrome)
D. Membranous nephropathy from HIV antigen deposition
E. Crystal nephropathy from atazanavir
Answer: C. Proximal renal tubular dysfunction (Fanconi syndrome)
Explanation: Tenofovir disoproxil fumarate causes proximal tubule dysfunction (Fanconi syndrome): renal phosphate wasting (low phosphorus, bone pain from osteomalacia), glycosuria with normal serum glucose, proteinuria, and progressive kidney injury. Tenofovir alafenamide has lower renal toxicity and is preferred in patients with risk factors. The triad of bone pain, hypophosphatemia, and glycosuria is the giveaway.
Question 10.
A 26 year old man with no significant medical history presents to clinic asking about HIV prevention. He is in a serodiscordant relationship and his partner is HIV positive with an undetectable viral load on ART. Which of the following is the most appropriate recommendation?
A. No intervention is needed because the partner has undetectable viral load
B. Condoms alone are sufficient
C. Start daily tenofovir plus emtricitabine as PrEP
D. Start a full 3 drug antiretroviral regimen
E. Postpone any sexual activity until the partner clears the virus
Answer: C. Start daily tenofovir plus emtricitabine as PrEP
Explanation: Pre exposure prophylaxis with daily tenofovir and emtricitabine (Truvada) or tenofovir alafenamide and emtricitabine (Descovy) is recommended for HIV negative individuals at substantial risk, including those in serodiscordant relationships. While U equals U is true for the positive partner on suppressive ART (A is partly correct in theory), PrEP adds a second layer of protection. Long acting injectable cabotegravir every 2 months is an alternative. Three drug ART (D) is treatment, not prevention. The virus does not clear (E).
HIV-1 is the global pandemic strain, more virulent and more transmissible. HIV-2 is largely confined to West Africa, has slower disease progression, lower viral loads, and is intrinsically resistant to NNRTIs (efavirenz, nevirapine, rilpivirine). The 4th generation immunoassay and the differentiation assay both detect HIV-2. ART regimens for HIV-2 must use NRTIs, INSTIs, and PIs, never NNRTIs.
AIDS is defined by either a CD4 count below 200 cells per microliter or the presence of any AIDS defining illness regardless of CD4 count. AIDS defining illnesses include Pneumocystis pneumonia, esophageal candidiasis, Kaposi sarcoma, primary CNS lymphoma, disseminated MAC, CMV end organ disease, cryptococcosis, toxoplasmosis, and HIV wasting syndrome.
The 4th generation test detects both p24 antigen (the viral capsid protein circulating in serum) and anti HIV antibodies. p24 antigen appears 7 to 10 days before antibody seroconversion, which shortens the window period. Older 3rd generation tests detected only antibodies and missed early acute infection. The 4th generation test has sensitivity and specificity above 99 percent.
Modern first line antiretroviral therapy combines two NRTIs (typically tenofovir alafenamide plus emtricitabine, or tenofovir disoproxil plus emtricitabine) with one integrase strand transfer inhibitor (bictegravir or dolutegravir). Common single tablet regimens include Biktarvy (bictegravir plus TAF plus emtricitabine) and Triumeq (dolutegravir plus abacavir plus lamivudine). INSTI based regimens have high genetic barriers to resistance and excellent tolerability.
Pre exposure prophylaxis uses daily tenofovir plus emtricitabine, or every 2 month injectable cabotegravir, to prevent HIV acquisition in high risk individuals. Indications include serodiscordant partnerships, multiple sexual partners with inconsistent condom use, and injection drug use. PrEP reduces sexual transmission by approximately 99 percent with strict adherence. Patients on PrEP require HIV testing every 3 months because using PrEP in undiagnosed acute HIV causes resistance.
Trimethoprim sulfamethoxazole has activity against both Pneumocystis jirovecii (the AIDS pneumonia) and Toxoplasma gondii (the AIDS encephalitis). Starting TMP SMX at CD4 less than 200 for PCP coverage incidentally provides Toxoplasma prophylaxis when CD4 falls below 100, which is convenient and is the reason a single daily double strength tablet remains the universal default in advanced HIV.
U equals U is the scientific consensus that a person with HIV on suppressive antiretroviral therapy who maintains an undetectable viral load (below 200 copies per mL) cannot sexually transmit the virus to others. The evidence comes from large prospective studies (PARTNER, Opposites Attract, HPTN 052). This concept is now testable on Step 1.
HIV is an enveloped, single stranded RNA retrovirus that uses gp120 to bind CD4 and CCR5 or CXCR4 to enter T helper cells. Reverse transcriptase converts RNA to DNA, integrase inserts the DNA into the host genome, and protease cleaves polyproteins to produce mature virions. Each step is a drug target. Diagnose HIV with a 4th generation antigen and antibody immunoassay, confirm with an antibody differentiation assay, and use HIV RNA for discordant or acute cases. CD4 count drives the opportunistic infection ladder. PCP and Toxo enter at CD4 less than 200 and 100 respectively, both prevented with TMP SMX. CMV and MAC appear at CD4 less than 50. First line ART is two NRTIs plus one INSTI. PrEP and PEP use tenofovir based regimens.
If you want this level of clarity across every Step 1 topic, our IMG Helping Hands structured prep program is built specifically for international medical graduates working toward the US match.
This article is part of our USMLE Step 1 microbiology series. Continue with our companion guides:
• Gram Positive vs Gram Negative Bacteria: The Simplest Way to Master Step 1 Questions
• How to Remember Antibiotics and Their Mechanisms for Step 1 (Fast and High Yield)
• Best 3, 6, and 12 Month Study Plans for USMLE Step 1
1. National Board of Medical Examiners. USMLE Step 1 Content Outline. 2025 revision.
2. Le T, Bhushan V. First Aid for the USMLE Step 1 2025. McGraw Hill, 35th edition.
3. Centers for Disease Control and Prevention. Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations. 2014 algorithm (current).
4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services, 2024.
5. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. NIH, CDC, HIVMA of IDSA, 2024.
6. Rodger AJ, Cambiano V, Bruun T, et al. Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV Positive Partner Is Using Suppressive Antiretroviral Therapy (PARTNER study). JAMA. 2016:316(2):171 to 181.
7. Bavinton BR, Pinto AN, Phanuphak N, et al. Viral suppression and HIV transmission in serodiscordant male couples (Opposites Attract study). Lancet HIV. 2018:5(8):e438 to e447.
8. Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral Therapy for the Prevention of HIV-1 Transmission (HPTN 052). N Engl J Med. 2016:375(9):830 to 839.
9. Mallal S, Phillips E, Carosi G, et al. HLA B*5701 screening for hypersensitivity to abacavir (PREDICT-1). N Engl J Med. 2008:358(6):568 to 579.
10. Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women (HPTN 083). N Engl J Med. 2021:385(7):595 to 608.
11. Sketchy Medical. Microbiology video collection: HIV virion, life cycle, opportunistic infections, and antiretroviral mechanisms.
12. Le T, Bhushan V. First Aid Q and A for the USMLE Step 1. McGraw Hill, current edition.
ABOUT IMG HELPING HANDS
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